Tricyclic heterocycles as fgfr inhibitors

ABSTRACT

The present disclosure relates to tricyclic heterocycles, and pharmaceutical compositions of the same, that are inhibitors of the FGFR enzyme and are useful in the treatment of FGFR-associated diseases such as cancer.

FIELD

The present disclosure relates to tricyclic heterocycles, andpharmaceutical compositions of the same, that are inhibitors of theenzyme FGFR and are useful in the treatment of FGFR-associated diseasessuch as cancer.

SEQUENCE LISTING

This application contains a Sequence Listing that has been submittedelectronically as an ASCII text file named “Sequence_Listing.txt.” TheASCII text file, created on Jun. 6, 2022, is 1 kilobyte in size. Thematerial in the ASCII text file is hereby incorporated by reference inits entirety.

BACKGROUND

The Fibroblast Growth Factor Receptors (FGFR) are receptor tyrosinekinases that bind to fibroblast growth factor (FGF) ligands. There arefour FGFR proteins (FGFR1-4) that are capable of binding ligands and areinvolved in the regulation of many physiological processes includingtissue development, angiogenesis, wound healing, and metabolicregulation. Upon ligand binding, the receptors undergo dimerization andphosphorylation leading to stimulation of the protein kinase activityand recruitment of many intracellular docking proteins. Theseinteractions facilitate the activation of an array of intracellularsignaling pathways including Ras-MAPK, AKT-PI3K, and phospholipase Cthat are important for cellular growth, proliferation and survival(Reviewed in Eswarakumar et al. Cytokine & Growth Factor Reviews, 2005,16, 139-149). Aberrant activation of this pathway either throughoverexpression of FGF ligands or FGFR or activating mutations in theFGFRs can lead to tumor development, progression, and resistance toconventional cancer therapies. In human cancer, genetic alterationsincluding gene amplification, chromosomal translocations and somaticmutations that lead to ligand-independent receptor activation have beendescribed (Reviewed in Knights and Cook, Pharmacology & Therapeutics,2010, 125, 105-117; Turner and Grose, Nature Reviews Cancer, 2010, 10,116-129). Large scale DNA sequencing of thousands of tumor samples hasrevealed that FGFR genes are altered in many cancers (Helsten et al.Clin Cancer Res. 2016, 22, 259-267). Some of these activating mutationsare identical to germline mutations that lead to skeletal dysplasiasyndromes (Gallo et al. Cytokine & Growth Factor Reviews 2015, 26,425-449). Mechanisms that lead to aberrant ligand-dependent signaling inhuman disease include overexpression of FGFs and changes in FGFRsplicing that lead to receptors with more promiscuous ligand bindingabilities. Therefore, development of inhibitors targeting FGFR may beuseful in the clinical treatment of diseases that have elevated FGF orFGFR activity.

The cancer types in which FGF/FGFRs are implicated include, but are notlimited to: carcinomas (e.g., bladder, breast, colorectal, endometrial,gastric, head and neck, kidney, lung, ovarian, prostate); hematopoieticmalignancies (e.g., multiple myeloma, acute myelogenous leukemia, andmyeloproliferative neoplasms); and other neoplasms (e.g., glioblastomaand sarcomas). In addition to a role in oncogenic neoplasms, FGFRactivation has also been implicated in skeletal and chondrocytedisorders including, but not limited to, achrondroplasia andcraniosynostosis syndromes.

There is a continuing need for the development of new drugs for thetreatment of cancer, and the FGFR inhibitors described herein helpaddress this need.

SUMMARY

The present disclosure is directed to compounds having Formula (I):

or pharmaceutically acceptable salts thereof, wherein constituentvariables are defined herein.

The present disclosure is further directed to pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.

The present disclosure is further directed to methods of inhibiting anFGFR enzyme (e.g., an FGFR3 enzyme) comprising contacting the enzymewith a compound of Formula (I), or a pharmaceutically acceptable saltthereof.

The present disclosure is further directed to a method of treating adisease associated with abnormal activity or expression of an FGFRenzyme (e.g., an FGFR3 enzyme), comprising administering a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, to a patientin need thereof.

The present disclosure is further directed to compounds of Formula (I)for use in treating a disease associated with abnormal activity orexpression of an FGFR enzyme (e.g., an FGFR3 enzyme). The presentdisclosure is further directed to the use of compounds of Formula (I) inthe preparation of a medicament for use in therapy.

The present disclosure is further directed to a method for treating adisorder mediated by an FGFR enzyme (e.g., an FGFR3 enzyme), or a mutantthereof, in a patient in need thereof, comprising the step ofadministering to said patient a compound of Formula (I), orpharmaceutically acceptable composition thereof.

The present disclosure is further directed to a method for treating adisorder mediated by an FGFR enzyme (e.g., an FGFR3 enzyme), or a mutantthereof, in a patient in need thereof, comprising the step ofadministering to the patient a compound of Formula (I), or apharmaceutically acceptable salt thereof, or a composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof,in combination with another therapy or therapeutic agent as describedherein.

DETAILED DESCRIPTION Compounds

In one aspect, the present disclosure provides compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹⁰;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NOR^(a2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2) S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²⁰;

R³ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NOR^(a3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R³⁰;

R⁴ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NOR^(a4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C6-aryl-C₁₋₃ alkylene and 5-10 memberedheteroaryl-C₁₋₃ alkylene are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R⁴⁰;

R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NOR^(a5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁵⁰;

Z is N or CR⁶;

R⁶ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6), C(═NR^(e6))R^(b6),C(═NOR^(a6))R^(b6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁶⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a10), SR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10),C(O)OR^(a10), OC(O)R^(b10), OC(O)NR^(c10)R^(d10), NR^(c10)R^(d10),NR^(c10)C(O)R^(b10), NR^(c10)C(O)OR^(a10), NR^(c10)C(O)NR^(c10)R^(d10),C(═NR^(e10))R^(b10), C(═NOR^(a10))R^(b10), C(═NR^(e10))NR^(c10)R^(d10),NR^(c10)C(═NR^(e10))NR^(c10)R^(d10), NR^(c10)S(O)R^(b10),NR^(c10)S(O)₂R^(b10), NR^(c10)S(O)₂NR^(c10)R^(d10), S(O)R^(b10),S(O)NR^(c10)R^(d10), S(O)₂R^(b10), and S(O)₂NR^(c10)R^(d10); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a11), SR^(a11), C(O)R^(a11), C(O)NR^(c11)R^(d11),C(O)OR^(a11), NR^(c11)R^(d11), NR^(c11)C(O)R^(b11),NR^(c11)C(O)OR^(a11), NR^(c11)C(O)NR^(c11)R^(d11), NR^(c11)S(O)R^(b11),NR^(c11)S(O)₂R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11), S(O)R^(b11),S(O)NR^(c11)R^(d11), S(O)₂R^(b11), and S(O)₂NR^(c11)R^(d11); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a12),SR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12), C(O)OR^(a12),NR^(c12)R^(d12), NR^(c12)C(O)R^(b12), NR^(c12)C(O)OR^(a12),NR^(c12)C(O)NR^(c12)R^(d12), NR^(c12)S(O)R^(b12), NR^(c12)S(O)₂R^(b12),NR^(c12)S(O)₂NR^(c12)R^(d12), S(O)R^(b12), S(O)NR^(c12)R^(d12),S(O)₂R^(b12), and S(O)₂NR^(c12)R^(d12); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a20), SR^(a20), C(O)R^(b20), C(O)NR^(c20)R^(d20),C(O)OR^(a20), OC(O)R^(b20), OC(O)NR^(c20)R^(d20), NR^(c20)R^(d20),NR^(c20)C(O)R^(b20), NR^(c20)C(O)OR^(a20), NR^(c20)C(O)NR^(c20)R^(d20),C(═NR^(e20))R^(b20), C(═NOR^(a20))R^(b20), C(═NR^(e20))NR^(c20)R^(d20),NR^(c20)C(═NR^(e20))NR^(c20)R^(d20), NR^(c20)S(O)R^(b20),NR^(c20)S(O)₂R^(b20), NR^(c20)S(O)₂NR^(c20)R^(d20), S(O)R^(b20),S(O)NR^(c20)R^(d20), S(O)₂R^(b20), and S(O)₂NR^(c20)R^(d20); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a21), SR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)OR^(a21), NR^(c21)R^(d21), NR^(c21)C(O)R^(b21),NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21), NR^(c21)S(O)R^(b21),NR^(c21)S(O)₂R^(b21), NR^(c21)S(O)₂NR^(c21)R^(d21), S(O)R^(b21),S(O)NR^(c21)R^(d21), S(O)₂R^(b21), and S(O)₂NR^(c21)R^(d21); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a22),SR^(a22), C(O)R^(b22), C(O)NR^(c22)R^(d22), C(O)OR^(a22),NR^(c22)R^(d22), NR^(c22)C(O)R^(b22), NR^(c22)C(O)OR^(a22),NR^(c22)C(O)NR^(c22)R^(d22), NR^(c22)S(O)R^(b22), NR^(c22)S(O)₂R^(b22),NR^(c22)S(O)₂NR^(c22)R^(d22), S(O)R^(b22), S(O)NR^(c22)R^(d22),S(O)₂R^(b22), and S(O)₂NR^(c22)R^(d22); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryland 4-7 membered heterocycloalkyl, are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R^(g);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a30), SR^(a30), C(O)R^(b30), C(O)NR^(c30)R^(d30),C(O)OR^(a30), OC(O)R^(b30), OC(O)NR^(c30)R^(d30), NR^(c30)R^(d30),NR^(c30)C(O)R^(b30), NR^(c30)C(O)OR^(a30), NR^(c30)C(O)NR^(c30)R^(d30),C(═NR^(e30))R^(b30), C(═NOR^(a30))R^(b30), C(═NR^(e30))NR^(c30)R^(d30),NR^(c30)C(═NR^(e30))NR^(c30)R^(d30), NR^(c30)S(O)R^(b30),NR^(c30)S(O)₂R^(b30), NR^(c30)S(O)₂NR^(c30)R^(d30), S(O)R^(b30),S(O)NR^(c30)R^(d30), S(O)₂R^(b30), and S(O)₂NR^(c30)R^(d30); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³¹;

each R³¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a31), SR^(a31), C(O)R^(b31), C(O)NR^(c31)R^(d31),C(O)OR^(a31), NR^(c31)R^(d31), NR^(c31)C(O)R^(b31),NR^(c31)C(O)OR^(a31), NR^(c31)C(O)NR^(c31)R^(d31), NR^(c31)S(O)R^(b31),NR^(c31)S(O)₂R^(b31), NR^(c31)S(O)₂NR^(c31)R^(d31), S(O)R^(b31),S(O)NR^(c31)R^(d31), S(O)₂R^(b31), and S(O)₂NR^(c31)R^(d31); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³²;

each R³² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a32),SR^(a32), C(O)R^(b32), C(O)NR^(c32)R^(d32), C(O)OR^(a32),NR^(c32)R^(d32), NR^(c32)C(O)R^(b32), NR^(c32)C(O)OR^(a32),NR^(c32)C(O)NR^(c32)R^(d32), NR^(c32)S(O)R^(b32), NR^(c32)S(O)₂R^(b32),NR^(c32)S(O)₂NR^(c32)R^(d32), S(O)R^(b32), S(O)NR^(c32)R^(d32),S(O)₂R^(b32), and S(O)₂NR^(c32)R^(d32); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

each R⁴⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a40), SR^(a40), C(O)R^(b40), C(O)NR^(c40)R^(d40),C(O)OR^(a40), C(O)R^(b40), OC(O)NR^(c40)R^(d40), NR^(c40)R^(d40),NR^(c40)C(O)R^(b40), NR^(c40)C(O)OR^(a40), NR^(c40)C(O)NR^(c40)R^(d40),C(═NR^(e40))R^(b40), C(═NOR^(a40))R^(b40), C(═NR^(e40))NR^(c40)R^(d40),NR^(c40)C(═NR^(e40))NR^(c40)R^(d40), NR^(c40)S(O)R^(b40),NR^(c40)S(O)₂R^(b40), NR^(c40)S(O)₂NR^(c40)R^(d40), S(O)R^(b40),S(O)NR^(c40)R^(d40), S(O)₂R^(b40), and S(O)₂NR^(c40)R^(d40); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴¹;

each R⁴¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a41), SR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)OR^(a41), NR^(c41)R^(d41), NR^(c41)C(O)R^(b41),NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41), NR^(c41)S(O)R^(b41),NR^(c41)S(O)₂R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)R^(b41),S(O)NR^(c41)R^(d41), S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴²;

each R⁴² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a42),SR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42),NR^(c42)R^(d42), NR^(c42)C(O)R^(b42), NR^(c42)C(O)OR^(a42),NR^(c42)C(O)NR^(c42)R^(d42), NR^(c42)S(O)R^(b42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)R^(b42), S(O)NR^(c42)R^(d42),S(O)₂R^(b42), and S(O)₂NR^(c42)R^(d42); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

each R⁵⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a50), SR^(a50), C(O)R^(b50), C(O)NR^(c50)R^(d50),C(O)OR^(a50), OC(O)R^(b50), OC(O)NR^(c50)R^(d50), NR^(c50)R^(d50),NR^(c50)C(O)R^(b50), NR^(c50)C(O)OR^(a50), NR^(c50)C(O)NR^(c50)R^(d50),C(═NR^(e50))R^(b50), C(═NOR^(a50))R^(b50), C(═NR^(e50))NR^(c50)R^(d50),NR^(c50)C(═NR^(e50))NR^(c50)R^(d50), NR^(c50)S(O)R^(b50),NR^(c50)S(O)₂R^(b50), NR^(c50)S(O)₂NR^(c50)R^(d50), S(O)R^(b50),S(O)NR^(c50)R^(d50), S(O)₂R^(b50), and S(O)₂NR^(c50)R^(d50); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁵¹;

each R⁵¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a51), SR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51),C(O)OR^(a51), NR^(c51)R^(d51), NR^(c51)C(O)R^(b51),NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51), NR^(c51)S(O)R^(b51),NR^(c51)S(O)₂R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)R^(b51),S(O)NR^(c51)R^(d51), S(O)₂R^(b51), and S(O)₂NR^(c51)R^(d51); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁵²;

each R⁵² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a52),SR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52), C(O)OR^(a52),NR^(c52)R^(d52), NR^(c52)C(O)R^(b52), NR^(c52)C(O)OR^(a52),NR^(c52)C(O)NR^(c52)R^(d52), NR^(c52)S(O)R^(b52), NR^(c52)S(O)₂R^(b52),NR^(c52)S(O)₂NR^(c52)R^(d52), S(O)R^(b52), S(O)NR^(c52)R^(d52),S(O)₂R^(b52), and S(O)₂NR^(c52)R^(d52); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

each R⁶⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a60), SR^(a60), C(O)R^(b60), C(O)NR^(c60)R^(d60),C(O)OR^(a60), OC(O)R^(b60), OC(O)NR^(c60)R^(d60), NR^(c60)R^(d60),NR^(c60)C(O)R^(b60), NR^(c60)C(O)OR^(a60), NR^(c60)C(O)NR^(c60)R^(d60),C(═NR^(e60))R^(b60), C(═NOR^(a60))R^(b60), C(═NR^(e60))NR^(c60)R^(d60),NR^(c60)C(═NR^(e60))NR^(c60)R^(d60), NR^(c60)S(O)R^(b60),NR^(c60)S(O)₂R^(b60), NR^(c60)S(O)₂NR^(c60)R^(d60), S(O)R^(b60),S(O)NR^(c60)R^(d60), S(O)₂R^(b60), and S(O)₂NR^(c60)R^(d60); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁶¹;

each R⁶¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a61), SR^(a61), C(O)R^(b61), C(O)NR^(c61)R^(d61),C(O)OR^(a61), NR^(c61)R^(d61), NR^(c61)C(O)R^(b61),NR^(c61)C(O)OR^(a61), NR^(c61)C(O)NR^(c61)R^(d61), NR^(c61)S(O)R^(b61),NR^(c61)S(O)₂R^(b61), NR^(c61)S(O)₂NR^(c61)R^(d61), S(O)R^(b61),S(O)NR^(c61)R^(d61), S(O)₂R^(b61), and S(O)₂NR^(c61)R^(d61); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀-aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁶²;

each R⁶² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a62),SR^(a62), C(O)R^(b62), C(O)NR^(c62)R^(d62), C(O)OR^(a62),NR^(c62)R^(d62), NR^(c62)C(O)R^(b62), NR^(c62)C(O)OR^(a62),NR^(c62)C(O)NR^(c62)R^(d62), NR^(c62)S(O)R^(b62), NR^(c62)S(O)₂R^(b62),NR^(c62)S(O)₂NR^(c62)R^(d62), S(O)R^(b62), S(O)NR^(c62)R^(d62),S(O)₂R^(b62), and S(O)₂NR^(c62)R^(d62); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

each R^(a1), R^(b1), R^(c1) and R^(d1) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a2), R^(b2), R^(c2) and R^(d2) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²⁰;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²⁰;

each R^(e2) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a3), R^(b3), R^(c3) and R^(d3) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R³⁰;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R³⁰;

each R^(e3) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a4), R^(b4), R^(c4) and R^(d4) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁴⁰;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁴⁰;

each R^(e4) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a5), R^(b5), R^(c5) and R^(d5) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵⁰;

or any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵⁰;

each R^(e5) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a6), R^(b6), R^(c6) and R^(d6) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁶⁰;

or any R^(c6) and R^(d6) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁶⁰;

each R^(e6) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a10), R^(b10), R^(c10) and R^(d10) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

or any R^(c10) and R^(d10) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(e10) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a11), R^(b11), R^(c11) and R^(d11) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

or any R^(c11) and R^(d11) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(a12), R^(b12), R^(c12) and R^(d12) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a20), R^(b20), R^(c20) and R^(d20) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹;

or any R^(c20) and R^(d20) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹;

each R^(e20) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a21), R^(b21), R^(c21) and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²²;

or any R^(c21) and R^(d21) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²²;

each R^(a22), R^(b22), R^(c22) and R^(d22) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a30), R^(b30), R^(c30) and R^(d30) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R³¹;

or any R^(c30) and R^(d30) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R³¹;

each R^(e30) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a31), R^(b31), R^(c31) and R^(d31) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R³²;

or any R^(c31) and R^(d31) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R³²;

each R^(a32), R^(b32), R^(c32) and R^(d32) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a40), R^(b40), R^(c40) and R^(d40) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁴¹;

or any R^(c40) and R^(d40) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁴¹;

each R^(e40) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a41), R^(b41), R^(c41) and R^(d41) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁴²;

or any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R⁴²;

each R^(a42), R^(b42), R^(c42) and R^(d42) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a50), R^(b50), R^(c50) and R^(d50) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵¹;

or any R^(c50) and R^(d50) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵¹;

each R^(e50) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a51), R^(b51), R^(c51) and R^(d51) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵²;

or any R^(c51) and R^(d51) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R⁵²;

each R^(a52), R^(b52), R^(c52) and R^(d52) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a60), R^(b60), R^(c60) and R^(d60) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁶¹;

or any R^(c60) and R^(d60) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁶¹;

each R^(e60) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a61), R^(b61), R^(c61) and R^(d61) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁶²;

or any R^(c61) and R^(d61) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R⁶²;

each R^(a62), R^(b62), R^(c62) and R^(d62) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); and

each R^(g) is independently selected from D, OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkylcarbonyloxy,aminocarbonyloxy, C₁₋₆ alkylaminocarbonyloxy, di(C₁₋₆alkyl)aminocarbonyloxy, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments, Z is CR⁶. In some embodiments, Z is CH. In someembodiments, Z is N.

In some embodiments, R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(a1);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰.

In some embodiments, R¹ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰.

In some embodiments, R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroarylare each optionally substituted with 1 or 2 substituents independentlyselected from R¹⁰.

In some embodiments, R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, halo, D, CN, NO₂,OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroarylare each optionally substituted with 1 or 2 substituents independentlyselected from R¹⁰.

In some embodiments, R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰.

In some embodiments, R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰.

In some embodiments, R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1 or 2substituents independently selected from R¹⁰.

In some embodiments, R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰.

In some embodiments, R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹⁰.

In some embodiments, R¹ is selected from C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰.

In some embodiments, R¹ is selected from C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1 or 2substituents independently selected from R¹⁰.

In some embodiments, R¹ is selected from C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰.

In some embodiments, R¹ is selected from C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹⁰.

In some embodiments, R¹ is selected from C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein said C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl are each optionally substituted with 1 or 2 substituentsindependently selected from R¹⁰.

In some embodiments, R¹ is selected from phenyl and 5-6 memberedheteroaryl; wherein said phenyl and 5-6 membered heteroaryl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹⁰.

In some embodiments, R¹ is 5-6 membered heteroaryl, wherein said 5-6membered heteroaryl is optionally substituted with 1 or 2 substituentsindependently selected from R¹⁰.

In some embodiments, R¹ is selected from C₁₋₆ alkyl, C₂₋₆ alkynyl,phenyl, cyclohexenyl, pyrazol-4-yl, imidazol-4-yl,6-oxo-1,6-dihydropyridin-3-yl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, pyridin-3-yl, andpyrimidin-5-yl, each of which is optionally substituted with 1, 2, 3, or4 substituents independently selected from R¹⁰.

In some embodiments, R¹ is selected from C₁₋₆ alkyl, C₂₋₆ alkynyl,phenyl, cyclohexenyl, pyrazol-4-yl, imidazol-4-yl,6-oxo-1,6-dihydropyridin-3-yl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, pyridin-3-yl, andpyrimidin-5-yl, each of which is optionally substituted with 1 or 2substituents independently selected from R¹⁰.

In some embodiments, R¹ is selected from pyrazol-4-yl, imidazol-4-yl,6-oxo-1,6-dihydropyridin-3-yl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, pyridin-3-yl, andpyrimidin-5-yl, each of which is optionally substituted with 1, 2, 3, or4 substituents independently selected from R¹⁰.

In some embodiments, R¹ is selected from pyrazol-4-yl, imidazol-4-yl,6-oxo-1,6-dihydropyridin-3-yl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, pyridin-3-yl, andpyrimidin-5-yl, each of which is optionally substituted with 1 or 2substituents independently selected from R¹⁰.

In some embodiments, R¹ is pyrazolyl optionally substituted with 1 or 2substituents independently selected from R¹⁰. In some embodiments, R¹ ispyrazolyl substituted with 1 or 2 substituents independently selectedfrom R¹⁰.

In some embodiments, R¹ is phenyl optionally substituted with 1 or 2substituents independently selected from R¹⁰. In some embodiments, R¹ isphenyl substituted with 1 or 2 substituents independently selected fromR¹⁰.

In some embodiments, R¹ is selected from H,1-(2-hydroxyethyl)-1H-pyrazol-4-yl,1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl,1-(1-amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl,4-(morpholine-4-carbonyl)phenyl, 1H-pyrazol-4-yl,1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl,1-(2-hydroxybutyl)-1H-pyrazol-4-yl,1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl,1-((5-cyanopyridin-3-yl)methyl)-1H-pyrazol-4-yl,1-((2-cyanopyridin-4-yl)methyl)-1H-pyrazol-4-yl,1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl,1-(1-(2-cyanopyridin-4-yl)ethyl)-1H-pyrazol-4-yl,4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl,4-(1,1-dioxidothiomorpholino)phenyl,1-(pyrimidin-2-ylmethyl)-1H-pyrazol-4-yl,1-((6-cyanopyridin-2-yl)methyl)-1H-pyrazol-4-yl,4-(4-acetylpiperazin-1-yl)phenyl,4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl,4-((4-acetylpiperazin-1-yl)methyl)phenyl,4-((4-(2-hydroxyacetyl)piperazin-1-yl)methyl)phenyl,4-(4-methylpiperazin-1-yl)phenyl,4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl,1-(cyanomethyl)-1H-pyrazol-4-yl,1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, 1-benzyl-1H-pyrazol-4-yl,1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl,1-(1-cyanoethyl)-1H-pyrazol-4-yl, 1-(2,2-difluoroethyl)-1H-pyrazol-4-yl,1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl,1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl,1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl, 1-cyclopropyl-1H-pyrazol-4-yl,1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl,1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl,1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl,9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl,1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl,6-oxo-1,6-dihydropyridin-3-yl, 5-isopropyl-1H-pyrazol-4-yl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,5-(2-hydroxypropan-2-yl)pyridin-3-yl, 2-(methylamino)pyrimidin-5-yl,1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl,1-(2-morpholinoethyl)-1H-pyrazol-4-yl,1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl,1-(3-hydroxypropyl)-1H-pyrazol-4-yl, 1-(2-cyanoethyl)-1H-pyrazol-4-yl,1-(2-Amino-2-oxoethyl)-1H-pyrazol-4-yl,6-(2-hydroxypropan-2-yl)pyridin-3-yl,6-(2,2,2-trifluoroethyl)pyridin-3-yl, 6-(methylcarbamoyl)pyridin-3-yl,4-hydroxycyclohex-1-en-1-yl, 5-hydroxypent-1-yn-1-yl, and2-hydroxypropan-2-yl.

In some embodiments, R¹ is selected from1-(2-hydroxyethyl)-1H-pyrazol-4-yl,1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl,1-(1-amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl,4-(morpholine-4-carbonyl)phenyl, 1H-pyrazol-4-yl,1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl,1-(2-hydroxybutyl)-1H-pyrazol-4-yl,1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl,1-((5-cyanopyridin-3-yl)methyl)-1H-pyrazol-4-yl,1-((2-cyanopyridin-4-yl)methyl)-1H-pyrazol-4-yl,1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl,1-(1-(2-cyanopyridin-4-yl)ethyl)-1H-pyrazol-4-yl,4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl,4-(1,1-dioxidothiomorpholino)phenyl,1-(pyrimidin-2-ylmethyl)-1H-pyrazol-4-yl,1-((6-cyanopyridin-2-yl)methyl)-1H-pyrazol-4-yl,4-(4-acetylpiperazin-1-yl)phenyl,4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl,4-((4-acetylpiperazin-1-yl)methyl)phenyl,4-((4-(2-hydroxyacetyl)piperazin-1-yl)methyl)phenyl,4-(4-methylpiperazin-1-yl)phenyl,4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl,1-(cyanomethyl)-1H-pyrazol-4-yl,1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, 1-benzyl-1H-pyrazol-4-yl,1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl,1-(1-cyanoethyl)-1H-pyrazol-4-yl, 1-(2,2-difluoroethyl)-1H-pyrazol-4-yl,1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl,1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl,1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl, 1-cyclopropyl-1H-pyrazol-4-yl,1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl,1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl,1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl,9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl,1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl,6-oxo-1,6-dihydropyridin-3-yl, 5-isopropyl-1H-pyrazol-4-yl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,5-(2-hydroxypropan-2-yl)pyridin-3-yl, 2-(methylamino)pyrimidin-5-yl,1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl,1-(2-morpholinoethyl)-1H-pyrazol-4-yl,1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl,1-(3-hydroxypropyl)-1H-pyrazol-4-yl, 1-(2-cyanoethyl)-1H-pyrazol-4-yl,1-(2-Amino-2-oxoethyl)-1H-pyrazol-4-yl,6-(2-hydroxypropan-2-yl)pyridin-3-yl,6-(2,2,2-trifluoroethyl)pyridin-3-yl, 6-(methylcarbamoyl)pyridin-3-yl,4-hydroxycyclohex-1-en-1-yl, 5-hydroxypent-1-yn-1-yl, and2-hydroxypropan-2-yl.

In some embodiments, R¹ is selected from4-(morpholine-4-carbonyl)phenyl,4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl,4-(1,1-dioxidothiomorpholino)phenyl, 4-(4-acetylpiperazin-1-yl)phenyl,4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl,4-((4-acetylpiperazin-1-yl)methyl)phenyl,4-((4-(2-hydroxyacetyl)piperazin-1-yl)methyl)phenyl,4-(4-methylpiperazin-1-yl)phenyl, and4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl.

In some embodiments, R¹ is selected from1-(2-hydroxyethyl)-1H-pyrazol-4-yl,1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl,1-(1-amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl, 1H-pyrazol-4-yl,1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl,1-(2-hydroxybutyl)-1H-pyrazol-4-yl,1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl,1-((5-cyanopyridin-3-yl)methyl)-1H-pyrazol-4-yl,1-((2-cyanopyridin-4-yl)methyl)-1H-pyrazol-4-yl,1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl,1-(1-(2-cyanopyridin-4-yl)ethyl)-1H-pyrazol-4-yl,1-(pyrimidin-2-ylmethyl)-1H-pyrazol-4-yl,1-((6-cyanopyridin-2-yl)methyl)-1H-pyrazol-4-yl,1-(cyanomethyl)-1H-pyrazol-4-yl,1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, 1-benzyl-1H-pyrazol-4-yl,1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl,1-(1-cyanoethyl)-1H-pyrazol-4-yl, 1-(2,2-difluoroethyl)-1H-pyrazol-4-yl,1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl,1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl,1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl, 1-cyclopropyl-1H-pyrazol-4-yl,1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl,1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl,1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl,9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl,1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl,6-oxo-1,6-dihydropyridin-3-yl, 5-isopropyl-1H-pyrazol-4-yl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,5-(2-hydroxypropan-2-yl)pyridin-3-yl, 2-(methylamino)pyrimidin-5-yl,1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl,1-(2-morpholinoethyl)-1H-pyrazol-4-yl,1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl,1-(3-hydroxypropyl)-1H-pyrazol-4-yl, 1-(2-cyanoethyl)-1H-pyrazol-4-yl,1-(2-Amino-2-oxoethyl)-1H-pyrazol-4-yl,6-(2-hydroxypropan-2-yl)pyridin-3-yl,6-(2,2,2-trifluoroethyl)pyridin-3-yl, and6-(methylcarbamoyl)pyridin-3-yl.

In some embodiments, R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(b2), NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2). In some embodiments, R² is selected from H, C₁₋₆alkyl, halo, and CN.

In some embodiments, R² is H.

In some embodiments, R³ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), S(O)₂R^(b3), andS(O)₂NR^(c3)R^(d3). In some embodiments, R³ is selected from H, C₁₋₆alkyl, halo, and CN.

In some embodiments, R³ is H.

In some embodiments, R⁴ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), S(O)₂R^(b4), andS(O)₂NR^(c4)R^(d4). In some embodiments, R⁴ is selected from H, C₁₋₆alkyl, halo, and CN.

In some embodiments, R⁴ is H.

In some embodiments, R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁵⁰.

In some embodiments, R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1 or 2 substituents independently selected from R⁵⁰.

In some embodiments, R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, NO₂,OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl are each optionally substituted with1 or 2 substituents independently selected from R⁵⁰.

In some embodiments, R⁵ is selected from H, C₁₋₆ alkyl, and C₆₋₁₀ aryl;wherein said C₁₋₆ alkyl and C₆₋₁₀ aryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁵⁰. In someembodiments, R⁵ is selected from H, C₁₋₆ alkyl, and C₆₋₁₀ aryl; whereinsaid C₁₋₆ alkyl and C₆₋₁₀ aryl are each optionally substituted with 1 or2 substituents independently selected from R⁵⁰.

In some embodiments, R⁵ is selected from C₁₋₆ alkyl, and phenyl; whereinsaid C₁₋₆ alkyl and phenyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R⁵⁰. In some embodiments,R⁵ is selected from C₁₋₆ alkyl, and phenyl; wherein said C₁₋₆ alkyl andphenyl are each optionally substituted with 1 or 2 substituentsindependently selected from R⁵⁰.

In some embodiments, R⁵ is phenyl optionally substituted with 1, 2, 3,or 4 substituents independently selected from R⁵⁰. In some embodiments,R⁵ is phenyl optionally substituted with 1 or 2 substituentsindependently selected from R⁵⁰. In some embodiments, R⁵ is phenylsubstituted with 1 or 2 substituents independently selected from R⁵⁰.

In some embodiments, R⁵ is H, methyl or 2,6-dichlorophenyl. In someembodiments, R⁵ is methyl or 2,6-dichlorophenyl.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, NO₂, OR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10), C(O)OR^(a10),OC(O)R^(b10), NR^(c10)R^(d10), NR^(c10)C(O)R^(b10), S(O)₂R^(b10), andS(O)₂NR^(c10)R^(d10); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, NO₂, OR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10), C(O)OR^(a10),OC(O)R^(b10), NR^(c10)R^(d10), NR^(c10)C(O)R^(b10), S(O)₂R^(b10), andS(O)₂NR^(c10)R^(d10); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1 or 2substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, halo, D,CN, NO₂, OR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10), C(O)OR^(a10),OC(O)R^(b10), NR^(c10)R^(d10), NR^(c10)C(O)R^(b10), S(O)₂R^(b10), andS(O)₂NR^(c10)R^(d10); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted with 1 or 2substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,OR^(a10), C(O)NR^(c10)R^(d10), and NR^(c10)R^(d10); wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,OR^(a10), C(O)NR^(c10)R^(d10), and NR^(c10)R^(d10); wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl,OR^(a10), C(O)NR^(c10)R^(d10), and NR^(c10)R^(d10); wherein said C₁₋₆alkyl, C₃₋₆ cycloalkyl, and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, OR^(a10), C(O)NR^(c10)R^(d10), NR^(c10)R^(d10),1,1-dioxidotetrahydro-2H-thiopyranyl, 1,1-dioxidothiomorpholino,piperazinyl, tetrahydro-2H-pyranyl, piperidinyl, cyclopropyl,tetrahydrofuran-3-yl, and cyclohexenyl, each of which is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, OR^(a10), C(O)NR^(c10)R^(d10), NR^(c10)R^(d10),1,1-dioxidotetrahydro-2H-thiopyranyl, 1,1-dioxidothiomorpholino,piperazinyl, tetrahydro-2H-pyranyl, piperidinyl, cyclopropyl,tetrahydrofuran-3-yl, and cyclohexenyl, each of which is optionallysubstituted with 1 or 2 substituents independently selected from R¹¹.

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, OR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11),NR^(c11)R^(d11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11), andS(O)₂NR^(c11)R^(d11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, OR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11),NR^(c11)R^(d11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11), andS(O)₂NR^(c11)R^(d11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1 or 2substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, halo, D,CN, OR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11),NR^(c11)R^(d11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11), andS(O)₂NR^(c11)R^(d11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted with 1 or 2substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,CN, OR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), NR^(c11)R^(d11), andS(O)₂R^(b11); wherein said C₁₋₆ alkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,CN, OR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), NR^(c11)R^(d11), andS(O)₂R^(b11); wherein said C₁₋₆ alkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1 or 2 substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, CN,OR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), NR^(c11)R^(d11), andS(O)₂R^(b11); wherein said C₁₋₆ alkyl, 4-7 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-6 membered heteroaryl are each optionally substitutedwith 1 or 2 substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, CN,OR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), NR^(c11)R^(d11), andS(O)₂R^(b11); wherein said C₁₋₆ alkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl are each optionally substituted with1 or 2 substituents independently selected from R¹².

In some embodiments, each R¹² is independently selected from C₁₋₆ alkyl,halo, CN, OR^(a12), and C(O)R^(b12); wherein said C₁₋₆ alkyl isoptionally substituted with 1 or 2 substituents independently selectedfrom R^(g).

In some embodiments, each R¹² is independently selected from C₁₋₆ alkyl,halo, CN, OR^(a12), and C(O)R^(b12); wherein said C₁₋₆ alkyl isoptionally substituted with a substituent which is OH.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a20),C(O)R^(b20), C(O)NR^(c20)R^(d20), C(O)OR^(a20), OC(O)R^(b20),NR^(c20)R^(d20), NR^(c20)C(O)R^(b20), SS(O)₂R^(b20), andS(O)₂NR^(c20)R^(d20), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R²¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R²² is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R³⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a30),C(O)R^(b30), C(O)NR^(c30)R^(d30), C(O)OR^(a30), OC(O)R^(b30),NR^(c30)R^(d30), NR^(c30)C(O)R^(b30), S(O)₂R^(b30), andS(O)₂NR^(c30)R^(d30); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³¹.

In some embodiments, each R³⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R³¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R³² is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R⁴⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a40),C(O)R^(b40), C(O)NR^(c40)R^(d40), C(O)OR^(a40), OC(O)R^(b40),NR^(c40)R^(d40), NR^(c40)C(O)R^(b40), S(O)₂R^(b40), andS(O)₂NR^(c40)R^(d40); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴¹.

In some embodiments, each R⁴⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R⁴¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R⁴² is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R⁵⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a50), C(O)R^(b50), C(O)NR^(c50)R^(d50),C(O)OR^(a50), NR^(c50)R^(d50), NR^(c50)C(O)R^(b50), S(O)₂R^(b50), andS(O)₂NR^(c50)R^(d50).

In some embodiments, each R⁵⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R⁵⁰ is independently selected from halo.

In some embodiments, each R⁵⁰ is Cl.

In some embodiments, each R⁵¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R⁵² is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R⁶⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a60),C(O)R^(b60), C(O)NR^(c60)R^(d60), C(O)OR^(a60), OC(O)R^(b60),NR^(c60)R^(d60), NR^(c60)C(O)R^(b60), S(O)₂R^(b60), andS(O)₂NR^(c60)R^(d60); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁶¹.

In some embodiments, each R⁶⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R⁶¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R⁶² is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, and CN.

In some embodiments, each R^(a1), R^(b1), R^(c1) and R^(d1) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a2), R^(b2), R^(c2) and R^(d2) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a3), R^(b3), R^(c3) and R^(d3) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a4), R^(b4), R^(c4) and R^(d4) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a5), R^(b5), R^(c5) and R^(d5) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a6), R^(b6), R^(c6) and R^(d6) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a10), R^(b10), R^(c10) and R^(d10) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, any R^(c10) and R^(d10) attached to the same Natom, together with the N atom to which they are attached, form a 6- or7-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹. In some embodiments,any R^(c10) and R^(d10) attached to the same N atom, together with the Natom to which they are attached, form a 6- or 7-memberedheterocycloalkyl group.

In some embodiments, each R^(a11), R^(b11), R^(c11) and R^(d11) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a12), R^(b12), R^(c12) and R^(d12) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a20), R^(b20), R^(c20) and R^(d20) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a21), R^(b21), R^(c21) and R^(d21) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a22), R^(b22), R^(c22) and R^(d22) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a30), R^(b30), R^(c30) and R^(d30) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a31), R^(b31), R^(c31) and R^(d31) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a32), R^(b32), R^(c32) and R^(d32) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a40), R^(b40), R^(c40) and R^(d40) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a41), R^(b41), R^(c41) and R^(d41) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a42), R^(b42), R^(c42) and R^(d42) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a50), R^(b50), R^(c50) and R^(d50) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a51), R^(b51), R^(c51) and R^(d51) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a52), R^(b52), R^(c52) and R^(d52) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a60), R^(b60), R^(c60) and R^(d60) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a61), R^(b61), R^(c61) and R^(d61) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a62), R^(b62), R^(c62) and R^(d62) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(g) is OH.

In one aspect, the present disclosure provides compounds of Formula II:

or a pharmaceutically acceptable salt thereof, wherein Z, R¹, R², R³,and R⁴ are as defined herein.

In one aspect, the present disclosure provides compounds of FormulaIIIa:

or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴, R⁵,R⁶, and R¹⁰ are as defined herein.

In one aspect, the present disclosure provides compounds of FormulaIIIb:

or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴, R⁵,R⁶, and R¹⁰ are as defined herein.

In one aspect, the present disclosure provides compounds of Formula IVa:

or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴, R⁶,and R¹⁰ are as defined herein.

In one aspect, the present disclosure provides compounds of Formula IVb:

or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴, R⁶,and R¹⁰ are as defined herein.

In some embodiments,

R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, halo, D, CN, NO₂, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), NR^(c1)R^(d1),NR^(c1)C(O)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, D, CN, NO₂, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R³ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, D, CN, NO₂, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

R⁴ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, D, CN, NO₂, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, halo, D, CN, NO₂, OR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵⁰;

Z is CR⁶;

R⁶ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, D, CN, NO₂, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10), C(O)OR^(a10),OC(O)R^(b10), NR^(c10)R^(d10), NR^(c10)C(O)R^(b10), S(O)₂R^(b10), andS(O)₂NR^(c10)R^(d10); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,OR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11),NR^(c11)R^(d11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11), andS(O)₂NR^(c11)R^(d11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a12),C(O)R^(b12), C(O)NR^(c12)R^(d12), C(O)OR^(a12), NR^(c12)R^(d12),NR^(c12)C(O)R^(b12), S(O)NR^(c12)R^(d12), S(O)₂R^(b12), andS(O)₂NR^(c12)R^(d12); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

each R⁵⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a50), C(O)R^(b50), C(O)NR^(c50)R^(d50), C(O)OR^(a50),OC(O)R^(b50), NR^(c50)R^(d50), NR^(c50)C(O)R^(b50), S(O)₂R^(b50), andS(O)₂NR^(c50)R^(d50); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R^(SI);

each R⁵¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,OR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51), C(O)OR^(a5),NR^(c51)R^(d51), NR^(c51)C(O)R^(b51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁵²;

each R⁵² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a52),C(O)R^(b52), C(O)NR^(c52)R^(d52), C(O)OR^(a52), NR^(c52)R^(d52),NR^(c52)C(O)R^(b52), S(O)₂R^(b52), and S(O)₂NR^(c52)R^(d52); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

each R^(a1), R^(b1), R^(c1) and R^(d1) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

each R^(a2), R^(b2), R^(c2) and R^(d2) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²⁰;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²⁰;

each R^(a3), R^(b3), R^(c3) and R^(d3) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R³⁰;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R³⁰;

each R^(a4), R^(b4), R^(c4) and R^(d4) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁴⁰;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁴⁰;

each R^(a5), R^(b5), R^(c5) and R^(d5) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵⁰;

or any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵⁰;

each R^(a6), R^(b6), R^(c6) and R^(d6) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁶⁰;

or any R^(c6) and R^(d6) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁶⁰;

each R^(a10), R^(b10), R^(c10) and R^(d10) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

or any R^(c10) and R^(d10) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(a11), R^(b11), R^(c11) and R^(d11) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

or any R^(c11) and R^(d11) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(a12), R^(b12), R^(c12) and R^(d12) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a50), R^(b50), R^(c50) and R^(d50) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵¹;

or any R^(c50) and R^(d50) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵¹;

each R^(a51), R^(b51), R^(c51) and R^(d51) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵²;

or any R^(c51) and R^(d51) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R⁵²;

each R^(a52), R^(b52), R^(c52) and R^(d52) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a60), R^(b60), R^(c60) and R^(d60) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁶¹;

or any R^(c60) and R^(d60) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁶¹; and

each R^(g) is independently selected from D, OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments,

R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, halo, D, CN, NO₂, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

R² is H;

R³ is H;

R⁴ is H;

R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, halo, D, CN, NO₂, OR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵⁰;

Z is CR⁶;

R⁶ is H;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10), C(O)OR^(a10),OC(O)R^(b10), NR^(c10)R^(d10), NR^(c10)C(O)R^(d10), S(O)₂R^(b10), andS(O)₂NR^(c10)R^(d10); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,OR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11),NR^(c11)R^(d11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11), andS(O)₂NR^(c11)R^(d11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a12),C(O)R^(b12), C(O)NR^(c12)R^(d12), C(O)OR^(a12), NR^(c12)R^(d12),NR^(c12)C(O)R^(b12), S(O)NR^(c12)R^(d12), S(O)₂R^(b12), andS(O)₂NR^(c12)R^(d12); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

each R⁵⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a50), C(O)R^(b50), C(O)NR^(c50)R^(d50), C(O)OR^(a50),OC(O)R^(b50), NR^(c50)R^(d50), NR^(c50)C(O)R^(b50), S(O)₂R^(b50), andS(O)₂NR^(c50)R^(d50); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁵¹;

each R⁵¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,OR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51), C(O)OR^(a51),NR^(c51)R^(d51), NR^(c51)C(O)R^(d51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁵²;

each R⁵² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a52),C(O)R^(b52), C(O)NR^(c52)R^(d52), C(O)OR^(a52), NR^(c52)R^(d52),NR^(c52)C(O)R^(b52), S(O)₂R^(b52), and S(O)₂NR^(c52)R^(d52); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

each R^(a1), R^(b1), R^(c1) and R^(d1) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

each R^(a5), R^(b5), R^(c5) and R^(d5) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵⁰;

or any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵⁰;

each R^(a10), R^(b10), R^(c10) and R^(d10) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

or any R^(c10) and R^(d10) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(a11), R^(b11), R^(c11) and R^(d11) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

or any R^(c11) and R^(d11) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(a12), R^(b12), R^(c12) and R^(d12) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a50), R^(b50), R^(c50) and R^(d50) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵¹;

or any R^(c50) and R^(d50) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵¹;

each R^(a51), R^(b51), R^(c51) and R^(d51) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵²;

or any R^(c51) and R^(d51) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R⁵²;

each R^(a52), R^(b52), R^(c52) and R^(d52) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); and

each R^(g) is independently selected from D, OH, CN, halo, C₁₋₆ alkyl,and C₁₋₆ haloalkyl.

In some embodiments,

R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

R² is H;

R³ is H;

R⁴ is H;

R⁵ is selected from H, C₁₋₆ alkyl, and C₆₋₁₀ aryl; wherein said C₁₋₆alkyl and C₆₋₁₀ aryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵⁰;

Z is CR⁶;

R⁶ is H;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, OR^(a10),C(O)NR^(c10)R^(d10), and NR^(c10)R^(d10); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, CN, OR^(a11),C(O)R^(b11), C(O)NR^(c11)R^(d11), NR^(c11)R^(d11), and S(O)₂R^(b11);wherein said C₁₋₆ alkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, halo, CN, OR^(a12),and C(O)R^(b12); wherein said C₁₋₆ alkyl is optionally substituted with1 or 2 substituents independently selected from R^(g);

each R⁵⁰ is independently selected from halo;

each Rao, R¹⁰ and R¹⁰ is independently selected from H and C₁₋₆ alkyl;wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

or any R^(c10) and R^(d10) attached to the same N atom, together withthe N atom to which they are attached, form a 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(a11), R^(b11), R^(c11) and R^(d11) is independently selectedfrom H and C₁₋₆ alkyl; wherein said C₁₋₆ alkyl is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹²;

each R^(a12) and R^(b12) is independently selected from H and C₁₋₆alkyl; wherein said C₁₋₆ alkyl is optionally substituted with R^(g); and

R^(g) is OH.

It is further appreciated that certain features of the disclosure, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the disclosure which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, substituents ofcompounds of the disclosure are disclosed in groups or in ranges. It isspecifically intended that the disclosure include each and everyindividual subcombination of the members of such groups and ranges.

For example, the term “C₁₋₆ alkyl” is specifically intended toindividually disclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, andC₆ alkyl.

At various places in the present specification various aryl, heteroaryl,cycloalkyl, and heterocycloalkyl rings are described. Unless otherwisespecified, these rings can be attached to the rest of the molecule atany ring member as permitted by valency. For example, the term “apyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl,or pyridin-4-yl ring.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

For compounds of the disclosure in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for R.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. A single divalent substituent,e.g., oxo, can replace two hydrogen atoms.

As used herein, the term “C_(i-j),” where i and j are integers, employedin combination with a chemical group, designates a range of the numberof carbon atoms in the chemical group with i-j defining the range. Forexample, C₁₋₆ alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6carbon atoms.

As used herein, the term “alkyl,” employed alone or in combination withother terms, refers to a saturated hydrocarbon group that may bestraight-chain or branched. An alkyl group formally corresponds to analkane with one C—H bond replaced by the point of attachment of thealkyl group to the remainder of the compound. In some embodiments, thealkyl group contains 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples ofalkyl moieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl, and the like. In some embodiments, the alkylgroup is methyl, ethyl, or propyl.

As used herein, the term “C_(i-j) alkylene,” employed alone or incombination with other terms, means a saturated divalent linkinghydrocarbon group that may be straight-chain or branched, having i to jcarbons. In some embodiments, the alkylene group contains from 1 to 4carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 carbon atoms.Examples of alkylene moieties include, but are not limited to, chemicalgroups such as methylene, ethylene, 1,1-ethylene, 1,2-ethylene,1,3-propylene, 1,2-propylene, 1,1-propylene, isopropylene, and the like.

As used herein, “alkenyl,” employed alone or in combination with otherterms, refers to a straight-chain or branched hydrocarbon groupcorresponding to an alkyl group having one or more carbon-carbon doublebonds. An alkenyl group formally corresponds to an alkene with one C—Hbond replaced by the point of attachment of the alkenyl group to theremainder of the compound. In some embodiments, the alkenyl moietycontains 2 to 6 or 2 to 4 carbon atoms. Example alkenyl groups include,but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl,sec-butenyl, and the like.

As used herein, “alkynyl,” employed alone or in combination with otherterms, refers to a straight-chain or branched hydrocarbon groupcorresponding to an alkyl group having one or more carbon-carbon triplebonds. An alkynyl group formally corresponds to an alkyne with one C—Hbond replaced by the point of attachment of the alkyl group to theremainder of the compound. In some embodiments, the alkynyl moietycontains 2 to 6 or 2 to 4 carbon atoms. Example alkynyl groups include,but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like.

As used herein, the terms “carbamoyl” and “carbamyl” interchangeablyrefer to a group of formula —C(O)NH₂.

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

The term “cyano” or “nitrile” refers to a group of formula —C≡N, whichalso may be written as —CN.

As used herein, the term “C₁₋₃ alkoxy-C₁₋₃ alkyl” refers to a group offormula —(C₁₋₃ alkylene)-(C₁₋₃ alkoxy).

As used herein, the term “C₁₋₃ alkoxy-C₁₋₃ alkoxy” refers to a group offormula —(C₁₋₃ alkoxylene)-(C₁₋₃ alkoxy).

As used herein, the term “HO—C₁₋₃ alkoxy” refers to a group of formula—(C₁₋₃ alkoxylene)-OH.

As used herein, the term “HO—C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-OH.

As used herein, the term “cyano-C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-CN.

As used herein, the term “H₂N—C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-NH₂.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyloxy” refers to a group offormula —OC(O)-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “aminocarbonyloxy” refers to a group of formula—OC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonyloxy” refers to agroup of formula —OC(O)NH-alkyl, wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms.

In some embodiments, each alkyl group has, independently, 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms.

In some embodiments, each alkyl group independently has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, “halo” or “halogen”, employed alone or in combinationwith other terms, includes fluoro, chloro, bromo, and iodo. In someembodiments, halo is F or Cl. In some embodiments, halo is F.

As used herein, the term “haloalkyl,” employed alone or in combinationwith other terms, refers to an alkyl group in which one or more of thehydrogen atoms has been replaced by a halogen atom, having up to thefull valency of halogen atom substituents, which may either be the sameor different. In some embodiments, the halogen atoms are fluoro atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms. Example haloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃,CHCl₂, C₂Cl₅, and the like.

As used herein, the term “alkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-alkyl. In some embodiments,the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examplealkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like. In some embodiments, alkoxy ismethoxy.

As used herein, “haloalkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-(haloalkyl). In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.An example haloalkoxy group is —OCF₃.

As used herein, “amino,” employed alone or in combination with otherterms, refers to NH₂.

As used herein, the term “alkylamino,” employed alone or in combinationwith other terms, refers to a group of formula —NH(alkyl). In someembodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms.Example alkylamino groups include methylamino, ethylamino, propylamino(e.g., n-propylamino and isopropylamino), and the like.

As used herein, the term “alkylthio,” employed alone or in combinationwith other terms, refers to a group of formula —S-alkyl. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “cycloalkyl,” employed alone or in combinationwith other terms, refers to a non-aromatic cyclic hydrocarbon includingcyclized alkyl and alkenyl groups. The term “C_(n-m) cycloalkyl” refersto a cycloalkyl that has n to m ring member carbon atoms. Cycloalkylgroups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused,bridged, or spiro rings) ring systems. Also included in the definitionof cycloalkyl are moieties that have one or more aromatic rings (e.g.,aryl or heteroaryl rings) fused (i.e., having a bond in common with) tothe cycloalkyl ring, for example, benzo derivatives of cyclopentane,cyclohexene, cyclohexane, and the like, or pyrido derivatives ofcyclopentane or cyclohexane. A cycloalkyl group containing a fusedaromatic ring can be attached through any ring-forming atom including aring-forming atom of the fused aromatic ring. Ring-forming carbon atomsof a cycloalkyl group can be optionally substituted by oxo. Cycloalkylgroups also include cycloalkylidenes. The term “cycloalkyl” alsoincludes bridgehead cycloalkyl groups (e.g., non-aromatic cyclichydrocarbon moieties containing at least one bridgehead carbon, such asadmantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatichydrocarbon moieties containing at least two rings fused at a singlecarbon atom, such as spiro[2.5]octane and the like). In someembodiments, the cycloalkyl group has 3 to 10 ring members, or 3 to 7ring members, or 3 to 6 ring members. In some embodiments, thecycloalkyl group is monocyclic or bicyclic. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is a C₃₋₇ monocyclic cycloalkyl group. In some embodiments, thecycloalkyl group is cyclopropyl or cyclohexenyl.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic ring or ringsystem, which may optionally contain one or more alkenylene oralkynylene groups as part of the ring structure, which has at least oneheteroatom ring member independently selected from nitrogen, sulfur,oxygen, and phosphorus, and which has 4-14 ring members, 4-10 ringmembers, 4-7 ring members, or 4-6 ring members. Included within the term“heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-memberedheterocycloalkyl groups. Heterocycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) orspirocyclic ring systems. In some embodiments, the heterocycloalkylgroup is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, sulfur and oxygen. Also includedin the definition of heterocycloalkyl are moieties that have one or morearomatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having abond in common with) to the non-aromatic heterocycloalkyl ring, forexample, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkylgroups can also include bridgehead heterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least one bridgehead atom, such asazaadamantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g.,a heterocycloalkyl moiety containing at least two rings fused at asingle atom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and thelike). In some embodiments, the heterocycloalkyl group has 3 to 10ring-forming atoms, 4 to 10 ring-forming atoms, or 3 to 8 ring formingatoms. In some embodiments, the heterocycloalkyl group has 1 to 5heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2heteroatoms. The carbon atoms or heteroatoms in the ring(s) of theheterocycloalkyl group can be oxidized to form a carbonyl, an N-oxide,or a sulfonyl group (or other oxidized linkage) or a nitrogen atom canbe quaternized. In some embodiments, the heterocycloalkyl portion is aC₂₇ monocyclic heterocycloalkyl group. In some embodiments, theheterocycloalkyl group is a morpholine ring, pyrrolidine ring,piperazine ring, piperidine ring, dihydropyran ring, tetrahydropyranring, tetrahyropyridine, azetidine ring, or tetrahydrofuran ring. Insome embodiments, the heterocycloalkyl is a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S. In some embodiments, theheterocycloalkyl is 4-10 membered heterocycloalkyl moiety having carbonand 1, 2, or 3 heteroatoms independently selected from N, O and S.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2 fusedrings) aromatic hydrocarbon moiety, such as, but not limited to, phenyl,1-naphthyl, 2-naphthyl, and the like. In some embodiments, aryl groupshave from 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments,the aryl group is a monocyclic or bicyclic group. In some embodiments,the aryl group is phenyl.

As used herein, the term “heteroaryl” or “heteroaromatic” employed aloneor in combination with other terms, refers to a monocyclic or polycyclic(e.g., having 2 or 3 fused rings) aromatic hydrocarbon moiety, havingone or more heteroatom ring members independently selected fromnitrogen, sulfur and oxygen. In some embodiments, the heteroaryl groupis a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, sulfur and oxygen. Exampleheteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl,thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl,benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl,1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl,indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl, pyridone, or the like. The carbon atoms orheteroatoms in the ring(s) of the heteroaryl group can be oxidized toform a carbonyl, an N-oxide, or a sulfonyl group (or other oxidizedlinkage) or a nitrogen atom can be quaternized, provided the aromaticnature of the ring is preserved. In some embodiments the heteroarylgroup is a 5 to 10 membered heteroaryl group. In another embodiment theheteroaryl group is a 5 to 6 membered heteroaryl group. In someembodiments, the heteroaryl is a 5-6 membered heteroaryl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS. In some embodiments, the heteroaryl is a 5-10 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S. In some embodiments, the heteroaryl has 5-6 ring atomsand 1 or 2 heteroatom ring members independently selected from nitrogen,sulfur and oxygen. In some embodiments, no more than 2 heteroatoms of a5-membered heteroaryl moiety are N.

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “oxidized” in reference to a ring-forming N atom refers to aring-forming N-oxide.

The term “oxidized” in reference to a ring-forming S atom refers to aring-forming sulfonyl or ring-forming sulfinyl.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized □ (pi) electrons where n is an integer).

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present disclosure. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out bymethods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids. Other resolvingagents suitable for fractional crystallization methods includestereoisomerically pure forms of methylbenzylamine (e.g., S and R forms,or diastereomerically pure forms), 2-phenylglycinol, norephedrine,ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the disclosure have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the disclosure also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, enamine—imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the disclosure also include all isotopes of atoms occurringin the intermediates or final compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. For example,isotopes of hydrogen include tritium and deuterium. One or moreconstituent atoms of the compounds of the disclosure can be replaced orsubstituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art (Deuterium Labeling in OrganicChemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts,1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau,Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007,7744-7765; The Organic Chemistry of Isotopic Labelling by James R.Hanson, Royal Society of Chemistry, 2011). Isotopically labeledcompounds can used in various studies such as NMR spectroscopy,metabolism experiments, and/or assays.

Substitution with heavier isotopes such as deuterium, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. (A. Kerekes et. al. J.Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm.2015, 58, 308-312).

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. The term is also meant to refer to compounds of thedisclosure, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,in the form of hydrates and solvates) or can be isolated. When in thesolid state, the compounds described herein and salts thereof may occurin various forms and may, e.g., take the form of solvates, includinghydrates. The compounds may be in any solid state form, such as apolymorph or solvate, so unless clearly indicated otherwise, referencein the specification to compounds and salts thereof should be understoodas encompassing any solid state form of the compound.

In some embodiments, the compounds of the disclosure, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of thedisclosure. Substantial separation can include compositions containingat least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 90%, at least about 95%, at least about 97%,or at least about 99% by weight of the compounds of the disclosure, orsalt thereof. Methods for isolating compounds and their salts areroutine in the art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present disclosure also includes pharmaceutically acceptable saltsof the compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present disclosure include the non-toxic saltsof the parent compound formed, for example, from non-toxic inorganic ororganic acids. The pharmaceutically acceptable salts of the presentdisclosure can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g.,methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) arepreferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); br (broad); Cbz (carboxybenzyl); calc. (calculated);d (doublet); dd (doublet of doublets); DCM (dichloromethane); DEAD(diethyl azodicarboxylate); DIAD (N,N′-diisopropyl azidodicarboxylate);DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); Et(ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography-mass spectrometry); m (multiplet); M (molar); mCPBA(3-chloroperoxybenzoic acid); MgSO₄ (magnesium sulfate); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); NaHCO₃ (sodium bicarbonate); NaOH (sodiumhydroxide); Na₂SO₄ (sodium sulfate); NH₄Cl (ammonium chloride); NH₄OH(ammonium hydroxide); NIS (N-iodosuccinimide); nM (nanomolar); NMR(nuclear magnetic resonance spectroscopy); OTf(trifluoromethanesulfonate); Pd (palladium); Ph (phenyl); pM(picomolar); PMB (para-methoxybenzyl), POCl₃ (phosphoryl chloride);RP-HPLC (reverse phase high performance liquid chromatography); s(singlet); SEM (2-trimethylsilylethoxymethyl); t (triplet or tertiary);TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet oftriplets); t-Bu (tert-butyl); TFA (trifluoroacetic acid); THF(tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM(micromolar); wt % (weight percent).

Synthesis

As will be appreciated by those skilled in the art, the compoundsprovided herein, including salts and stereoisomers thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the disclosure can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the disclosure can involve the protectionand deprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature,” “room temperature,” and “r.t.”,as used herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Compounds of Formula I can be prepared via the synthetic route asoutlined in Scheme 1.

Treatment of commercially available compound S-1 with an appropriatereagent, such as phosphoryl chloride (POCl₃), at elevated temperaturecan afford the compound S-2. Chloride displacement of compound S-2 vianucleophilic substitution with aqueous ammonia at elevated temperaturecan deliver compound S-3. Condensation of compound S-3 with compounds offormula S-4 (Hal is a halide, such as Cl, Br, or I) at elevatedtemperature can generate compounds S-5, which can undergo a reactionwith an appropriate reagent, such as N-iodosuccinimide (NIS), to affordcompounds S-6 (Hal is a halide, such as Cl, Br, or I). Compounds offormula S-6 can undergo a palladium-catalyzed carbonylation reactionwith CO (Angew. Chem. Int. Ed. 2009, 48, 4114-4133) to give a derivativeof formula S-7 and, upon elaboration using known organic synthesistechniques, can give rise to compounds of the formula S-8. Introductionof R² can then be achieved by the coupling of compounds S-8 with anadduct of formula S-9, in which M is a boronic acid, a boronic ester oran appropriate reagent [e.g., M is B(OR)₂, Sn(Alkyl)₃, Zn-Hal, etc.],under standard Suzuki cross-coupling conditions (e.g., in the presenceof a palladium catalyst and a suitable base) (Tetrahedron 2002, 58,9633-9695), or standard Stille cross-coupling conditions (e.g., in thepresence of a palladium catalyst) (ACS Catalysis 2015, 5, 3040-3053), orstandard Negishi cross-coupling conditions (e.g., in the presence of apalladium catalyst) (ACS Catalysis 2016, 6, 1540-1552) to affordcompounds S-10.

Methods of Use

Compounds of the present disclosure can inhibit the activity of the FGFRenzyme. For example, compounds of the present disclosure can be used toinhibit activity of an FGFR enzyme in a cell or in an individual orpatient in need of inhibition of the enzyme by administering aninhibiting amount of one or more compounds of the present disclosure tothe cell, individual, or patient. Compounds of the present disclosurecan be used to inhibit activity of the FGFR3 enzyme in a cell or in anindividual or patient in need of inhibition of the enzyme byadministering an inhibiting amount of one or more compounds of thepresent disclosure to the cell, individual, or patient. Compounds of thepresent disclosure can be used to inhibit activity of the FGFR2 enzymein a cell or in an individual or patient in need of inhibition of theenzyme by administering an inhibiting amount of one or more compounds ofthe present disclosure to the cell, individual, or patient. Compounds ofthe present disclosure can be used to inhibit the activity of an FGFR3and an FGFR2 enzyme in a cell or in an individual or patient in need ofinhibition of the enzyme by administering an inhibiting amount of acompound of the disclosure to the cell, individual, or patient.

As FGFR inhibitors, the compounds of the present disclosure are usefulin the treatment of various diseases associated with abnormal expressionor activity of the FGFR enzyme or FGFR ligands. Compounds which inhibitFGFR will be useful in providing a means of preventing the growth orinducing apoptosis in tumors, particularly by inhibiting angiogenesis.It is therefore anticipated that compounds of the present disclosurewill prove useful in treating or preventing proliferative disorders suchas cancers. In particular, tumors with activating mutants of receptortyrosine kinases or upregulation of receptor tyrosine kinases may beparticularly sensitive to the inhibitors.

In certain embodiments, the disclosure provides a method for treating aFGFR-mediated disorder in a patient in need thereof, comprising the stepof administering to said patient a compound according to the invention,or a pharmaceutically acceptable composition thereof.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure are selected from adenocarcinoma, bladder cancer,breast cancer, cervical cancer, cholangiocarcinoma, colorectal cancer,endometrial cancer, esophageal cancer, gall bladder cancer, gastriccancer, glioma, head and neck cancer, hepatocellular cancer, kidneycancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreaticcancer, prostate cancer, rhabdomyosarcoma, skin cancer, thyroid cancer,leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cellleukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's ornon-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, hairy celllymphoma, and Burkett's lymphoma.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure are selected from hepatocellular cancer, bladdercancer, breast cancer, cervical cancer, colorectal cancer, endometrialcancer, gastric cancer, head and neck cancer, kidney cancer, livercancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer,gall bladder cancer, pancreatic cancer, thyroid cancer, skin cancer,leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cellleukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's ornon-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, hairy celllymphoma, Burkett's lymphoma, glioblastoma, melanoma, and rhapdosarcoma.

In some embodiments, said cancer is selected from adenocarcinoma,bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma,endometrial cancer, gastric cancer, glioma, head and neck cancer, lungcancer, ovarian cancer, leukemia, and multiple myeloma.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure are selected from hepatocellular cancer, breastcancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lungcancer, prostate cancer, pancreatic cancer, testicular cancer, thyroidcancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterinecancer, and rhapdosarcoma.

A cancer characterized by an FGFR2 and/or FGFR3 alteration includesbladder cancers (FGFR3 mutation or fusion), cholangiocarcinoma (FGFR2fusion) and gastric cancer (FGFR2 amplification).

Compounds of the invention can be used to treat cancer patients withFGFR2/3 alterations, including mutations, fusion, rearrangement, andamplification. FGFR2/3 alterations were found in a subset ofcholangiocarcinoma, urothelial carcinoma, multiple myeloma, gastricadenocarcinoma, glioma, endometrial carcinoma, ovarian carcinoma,cervical cancer, lung cancer and breast cancer. Moreover, the compoundsof the invention can be used to target patients progressing on pan-FGFRinhibitor treatment due to acquirement of gatekeeper mutations(V555M/L/F/I in FGFR3, V564M/L/F/I in FGFR2). Also Compounds of theinvention can be used to treat cancer where FGFR2/3 signaling isinvolved in the resistance to other targeted therapies, for example, ithas the potential to overcome resistance to CDK4/6 inhibitors in ERpositive breast cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET), 8p11myeloproliferative syndrome), myelodysplasia syndrome (MDS), T-cellacute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-celllymphoma, adult T-cell leukemia, Waldenstrom's Macroglubulinemia, hairycell lymphoma, marginal zone lymphoma, chronic myelogenic lymphoma andBurkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma,lymphosarcoma, leiomyosarcoma, and teratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, mesothelioma, pavicellular and non-pavicellularcarcinoma, bronchial adenoma and pleuropulmonary blastoma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (exocrinepancreatic carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma,gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma,lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubularadenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer, gallbladder cancer and anal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma),bladder and urethra (squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma) and urothelial carcinoma.

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors Exemplary nervous system cancers include cancers of the skull(osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors, neuro-ectodermal tumors), and spinal cord(neurofibroma, meningioma, glioma, sarcoma), neuroblastoma,Lhermitte-Duclos disease and pineal tumors.

Exemplary gynecological cancers include cancers of the breast (ductalcarcinoma, lobular carcinoma, breast sarcoma, triple-negative breastcancer, HER2-positive breast cancer, inflammatory breast cancer,papillary carcinoma), uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma(serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers, tumors ofthe eye, tumors of the lips and mouth and squamous head and neck cancer.

The compounds of the present disclosure can also be useful in theinhibition of tumor metastases.

In addition to oncogenic neoplasms, the compounds of the invention areuseful in the treatment of skeletal and chondrocyte disorders including,but not limited to, achrondroplasia, hypochondroplasia, dwarfism,thanatophoric dysplasia (TD) (clinical forms TD I and TD II), Apertsyndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevensoncutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosissyndromes. In some embodiments, the present disclosure provides a methodfor treating a patient suffering from a skeletal and chondrocytedisorder.

In some embodiments, compounds described herein can be used to treatAlzheimer's disease, HIV, or tuberculosis.

As used herein, the term “8p11 myeloproliferative syndrome” is meant torefer to myeloid/lymphoid neoplasms associated with eosinophilia andabnormalities of FGFR1.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the FGFR enzyme with a compound described hereinincludes the administration of a compound described herein to anindividual or patient, such as a human, having FGFR, as well as, forexample, introducing a compound described herein into a samplecontaining a cellular or purified preparation containing the FGFRenzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent such as an amountof any of the solid forms or salts thereof as disclosed herein thatelicits the biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician. An appropriate“effective” amount in any individual case may be determined usingtechniques known to a person skilled in the art.

The phrase “pharmaceutically acceptable” is used herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, immunogenicity or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase “pharmaceutically acceptable carrier orexcipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. Excipients or carriers are generallysafe, non-toxic and neither biologically nor otherwise undesirable andinclude excipients or carriers that are acceptable for veterinary use aswell as human pharmaceutical use. In one embodiment, each component is“pharmaceutically acceptable” as defined herein. See, e.g., Remington:The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment (while the embodimentsare intended to be combined as if written in multiply dependent form).Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc.), and/or tyrosine kinase inhibitors can be used in combination withcompounds described herein for treatment of FGFR-associated diseases,disorders or conditions, or diseases or conditions as described herein.The agents can be combined with the present compounds in a single dosageform, or the agents can be administered simultaneously or sequentiallyas separate dosage forms.

Compounds described herein can be used in combination with one or moreother kinase inhibitors for the treatment of diseases, such as cancer,that are impacted by multiple signaling pathways. For example, acombination can include one or more inhibitors of the following kinasesfor the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG,PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR,HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT,FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron,Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3,EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL,ALK and B-Raf. Additionally, the solid forms of the FGFR inhibitor asdescribed herein can be combined with inhibitors of kinases associatedwith the PIK3/Akt/mTOR signaling pathway, such as PI3K, Akt (includingAkt1, Akt2 and Akt3) and mTOR kinases.

In some embodiments, compounds described herein can be used incombination with one or more inhibitors of the enzyme or proteinreceptors such as HPK1, SBLB, TUT4, A2A/A2B, CD47, CDK2, STING, ALK2,LIN28, ADAR1, MAT2a, RIOK1, HDAC8, WDR5, SMARCA2, and DCLK1 for thetreatment of diseases and disorders. Exemplary diseases and disordersinclude cancer, infection, inflammation and neurodegenerative disorders.

In some embodiments, compounds described herein can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include bromodomaininhibitors, the histone lysine methyltransferases, histone argininemethyl transferases, histone demethylases, histone deacetylases, histoneacetylases, and DNA methyltransferases. Histone deacetylase inhibitorsinclude, e.g., vorinostat.

For treating cancer and other proliferative diseases, compoundsdescribed herein can be used in combination with targeted therapies,including JAK kinase inhibitors (Ruxolitinib, additional JAK1/2 andJAK1-selective, baricitinib or INCB39110), Pim kinase inhibitors (e.g.,LGH447, INCB053914 and SGI-1776), PI3 kinase inhibitors includingPI3K-delta selective and broad spectrum PI3K inhibitors (e.g., INCB50465and INCB54707), PI3K-gamma inhibitors such as PI3K-gamma selectiveinhibitors, MEK inhibitors, CSF1R inhibitors (e.g., PLX3397 andLY3022855), TAM receptor tyrosine kinases inhibitors (Tyro-3, Axl, andMer; e.g., INCB81776), angiogenesis inhibitors, interleukin receptorinhibitors, Cyclin Dependent kinase inhibitors, BRAF inhibitors, mTORinhibitors, proteasome inhibitors (Bortezomib, Carfilzomib),HDAC-inhibitors (panobinostat, vorinostat), DNA methyl transferaseinhibitors, dexamethasone, bromo and extra terminal family membersinhibitors (for example, bromodomain inhibitors or BET inhibitors, suchas OTX015, CPI-0610, INCB54329 or INCB57643), LSD1 inhibitors (e.g.,GSK2979552, INCB59872 and INCB60003), arginase inhibitors (e.g.,INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat,NLG919 or BMS-986205), PARP inhibitors (e.g., olaparib or rucaparib),inhibitors of BTK such as ibrutinib, c-MET inhibitors (e.g.,capmatinib), an ALK2 inhibitor (e.g., INCB00928); or combinationsthereof.

For treating cancer and other proliferative diseases, compoundsdescribed herein can be used in combination with chemotherapeuticagents, agonists or antagonists of nuclear receptors, or otheranti-proliferative agents. Compounds described herein can also be usedin combination with a medical therapy such as surgery or radiotherapy,e.g., gamma-radiation, neutron beam radiotherapy, electron beamradiotherapy, proton therapy, brachytherapy, and systemic radioactiveisotopes.

Examples of suitable chemotherapeutic agents include any of: abarelix,abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole,aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine,bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide,bleomycin, bortezombi, bortezomib, brivanib, buparlisib, busulfanintravenous, busulfan oral, calusterone, camptosar, capecitabine,carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin,cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine,dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib,dactinomycin, daunorubicin, decitabine, degarelix, denileukin,denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel,doxorubicin, droloxafine, dromostanolone propionate, eculizumab,enzalutamide, epidophyllotoxin, epirubicin, epothilones, erlotinib,estramustine, etoposide phosphate, etoposide, exemestane, fentanylcitrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lonafarnib, lomustine, meclorethamine,megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin,paclitaxel, pamidronate, panitumumab, panobinostat, pazopanib,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pilaralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone,procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib,reloxafine, revlimid, rituximab, rucaparib, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur,temozolomide, teniposide, testolactone, tezacitabine, thalidomide,thioguanine, thiotepa, tipifamib, topotecan, toremifene, tositumomab,trastuzumab, tretinoin, triapine, trimidox, triptorelin, uracil mustard,valrubicin, vandetanib, vinblastine, vincristine, vindesine,vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

Cancer cell growth and survival can be impacted by dysfunction inmultiple signaling pathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors,chemokine receptor inhibitors, and phosphatase inhibitors, as well astargeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET,VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, CDK2, and CDK4/6 kinaseinhibitors such as, for example, those described in WO 2006/056399 canbe used in combination with the treatment methods and regimens of thepresent disclosure for treatment of cancers and solid tumors. Otheragents such as therapeutic antibodies can be used in combination withthe treatment methods and regimens of the present disclosure fortreatment of cancers and solid tumors. The one or more additionalpharmaceutical agents can be administered to a patient simultaneously orsequentially.

The treatment methods as disclosed herein can be used in combinationwith one or more other enzyme/protein/receptor inhibitors therapies forthe treatment of diseases, such as cancer and other diseases ordisorders described herein. For example, the treatment methods andregimens of the present disclosure can be combined with one or moreinhibitors of the following kinases for the treatment of cancer: Akt1,Akt2, Akt3, BCL2, CDK2, CDK4/6, TGF-□R, PKA, PKG, PKC, CaM-kinase,phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4,INS-R, IDH2, IGF-1R, IR-R, PDGF□R, PDGF□R, PI3K (alpha, beta, gamma,delta, and multiple or selective), CSF1R, KIT, FLK-II, KDR/FLK-1, FLK-4,fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB,TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR/Flt2, Flt4, EphA1,EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK,FRK, JAK, ABL, ALK and B-Raf. Non-limiting examples of inhibitors thatcan be combined with the treatment methods and regimens of the presentdisclosure for treatment of cancer include an FGFR inhibitor (FGFR1,FGFR2, FGFR3 or FGFR4, e.g., pemigatinib (INCB54828), INCB62079), anEGFR inhibitor (also known as ErB-1 or HER-1; e.g. erlotinib, gefitinib,vandetanib, orsimertinib, cetuximab, necitumumab, or panitumumab), aVEGFR inhibitor or pathway blocker (e.g. bevacizumab, pazopanib,sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib,vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), a PARP inhibitor(e.g. olaparib, rucaparib, veliparib or niraparib), a JAK inhibitor(JAK1 and/or JAK2, e.g., ruxolitinib, baricitinib, itacitinib(INCB39110), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDOinhibitor, a PI3K-delta inhibitor (e.g., INCB50465 and INCB50797), aPI3K-gamma inhibitor such as PI3K-gamma selective inhibitor, a Piminhibitor (e.g., INCB53914), a CSF1R inhibitor, a TAM receptor tyrosinekinases (Tyro-3, Axl, and Mer), an adenosine receptor antagonist (e.g.,A2a/A2b receptor antagonist), an HPK1 inhibitor, a chemokine receptorinhibitor (e.g. CCR2 or CCR5 inhibitor), a SHP1/2 phosphatase inhibitor,a histone deacetylase inhibitor (HDAC) such as an HDAC8 inhibitor, anangiogenesis inhibitor, an interleukin receptor inhibitor, bromo andextra terminal family members inhibitors (for example, bromodomaininhibitors or BET inhibitors such as INCB54329 and INCB57643), c-METinhibitors (e.g., capmatinib), an anti-CD19 antibody (e.g.,tafasitamab), an ALK2 inhibitor (e.g., INCB00928); or combinationsthereof.

In some embodiments, the treatment methods described herein are combinedwith administration of a PI3Kδ inhibitor. In some embodiments, thetreatment methods described herein are combined with administration of aJAK inhibitor. In some embodiments, the treatment methods describedherein are combined with administration of a JAK1 or JAK2 inhibitor(e.g., baricitinib or ruxolitinib). In some embodiments, the treatmentmethods described herein are combined with administration of a JAK1inhibitor. In some embodiments, the treatment methods described hereinare combined with administration of a JAK1 inhibitor, which is selectiveover JAK2.

Example antibodies that can be administered in combination therapyinclude, but are not limited to, trastuzumab (e.g., anti-HER2),ranibizumab (e.g., anti-VEGF-A), bevacizumab (AVASTIN™, e.g.,anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR),rituxan (e.g., anti-CD20), and antibodies directed to c-MET.

One or more of the following agents may be administered to a patient incombination with the treatment methods of the present disclosure and arepresented as a non-limiting list: a cytostatic agent, cisplatin,doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar,topotecan, paclitaxel, docetaxel, epothilones, tamoxifen,5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778,123, BMS 214662, IRESSA™ (gefitinib), TARCEVA™(erlotinib), antibodies to EGFR, intron, ara-C, adriamycin, cytoxan,gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan,chlorambucil, pipobroman, triethylenemelamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine,6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™(oxaliplatin), pentostatine, vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase,teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,estramustine, medroxyprogesteroneacetate, leuprolide, flutamide,toremifene, goserelin, carboplatin, hydroxyurea, amsacrine,procarbazine, mitotane, mitoxantrone, levamisole, navelbene,anastrazole, letrazole, capecitabine, reloxafine, droloxafine,hexamethylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™(tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan),TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine,porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan,trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab,C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine,aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1,fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, andMDL-101,731.

The treatment methods and regimens of the present disclosure can furtherbe used in combination with other methods of treating cancers, forexample by chemotherapy, irradiation therapy, tumor-targeted therapy,adjuvant therapy, immunotherapy or surgery. Examples of immunotherapyinclude cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2),CRS-207 immunotherapy, cancer vaccine, monoclonal antibody, bispecificor multi-specific antibody, antibody drug conjugate, adoptive T celltransfer, Toll receptor agonists, RIG-I agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor, PI3Kδ inhibitor and the like. The compounds can beadministered in combination with one or more anti-cancer drugs, such asa chemotherapeutic agent. Examples of chemotherapeutics include any ofabarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine,bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, busulfanintravenous, busulfan oral, calusterone, capecitabine, carboplatin,carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epacadostat, epirubicin, erlotinib,estramustine, etoposide phosphate, etoposide, exemestane, fentanylcitrate, filgrastim, floxuridine, fludarabine, fluorouracil,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinibditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate,levamisole, lomustine, meclorethamine, megestrol acetate, melphalan,mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab,oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase,pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin,procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib,sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,vorinostat, and zoledronate.

Additional examples of chemotherapeutics include proteosome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™),nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceuticallyacceptable salts. Other example suitable Bcr-Abl inhibitors include thecompounds, and pharmaceutically acceptable salts thereof, of the generaand species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S.Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib,linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib,crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and theirpharmaceutically acceptable salts. Other example suitable Flt-3inhibitors include compounds, and their pharmaceutically acceptablesalts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include dabrafenib, sorafenib, andvemurafenib, and their pharmaceutically acceptable salts. Other examplesuitable RAF inhibitors include compounds, and their pharmaceuticallyacceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062,VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptablesalts. Other example suitable FAK inhibitors include compounds, andtheir pharmaceutically acceptable salts, as disclosed in WO 04/080980,WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO01/014402.

Example suitable CDK4/6 inhibitors include palbociclib, ribociclib,trilaciclib, lerociclib, and abemaciclib, and their pharmaceuticallyacceptable salts. Other example suitable CDK4/6 inhibitors includecompounds, and their pharmaceutically acceptable salts, as disclosed inWO 09/085185, WO 12/129344, WO 11/101409, WO 03/062236, WO 10/075074,and WO 12/061156.

In some embodiments, the compounds of the disclosure can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the treatment methods of the disclosure can be usedin combination with a chemotherapeutic in the treatment of cancer, andmay improve the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the treatment methods of the disclosure can be usedin combination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). Additive or synergistic effects are desirableoutcomes of combining treatment methods of the present disclosure withan additional agent.

The agents can be combined with Compound 1 and/or antibody that binds tohuman PD-1 or human PD-L1, or antigen-binding fragment thereof, of thepresent treatment methods in a single or continuous dosage form, or theagents can be administered simultaneously or sequentially as separatedosage forms.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the treatment methods ofthe disclosure where the dexamethasone is administered intermittently asopposed to continuously.

The treatment methods described herein can be combined with anotherimmunogenic agent, such as cancerous cells, purified tumor antigens(including recombinant proteins, peptides, and carbohydrate molecules),cells, and cells transfected with genes encoding immune stimulatingcytokines. Non-limiting examples of tumor vaccines that can be usedinclude peptides of melanoma antigens, such as peptides of gp100, MAGEantigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected toexpress the cytokine GM-CSF.

The treatment methods described herein can be used in combination with avaccination protocol for the treatment of cancer. In some embodiments,the tumor cells are transduced to express GM-CSF. In some embodiments,tumor vaccines include the proteins from viruses implicated in humancancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBVand HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). In some embodiments,the treatment methods and regimens of the present disclosure can be usedin combination with tumor specific antigen such as heat shock proteinsisolated from tumor tissue itself. In some embodiments, the treatmentmethods described herein can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The treatment methods and regimens of the present disclosure can be usedin combination with bispecific macrocyclic peptides that target Fe alphaor Fe gamma receptor-expressing effectors cells to tumor cells. Thetreatment methods and regimens of the present disclosure can also becombined with macrocyclic peptides that activate host immuneresponsiveness.

In some further embodiments, the treatment methods of the disclosure arecombined with administration of other therapeutic agents to a patientprior to, during, and/or after a bone marrow transplant or stem celltransplant. The treatment methods and regimens of the present disclosurecan be used in combination with bone marrow transplant for the treatmentof a variety of tumors of hematopoietic origin.

When more than one pharmaceutical agents is administered to a patient,as discussed in any of the above embodiments, they can be administeredsimultaneously, separately, sequentially, or in combination (e.g., formore than two agents).

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

In some embodiments, compounds described herein can be used incombination with immune checkpoint inhibitors. Exemplary immunecheckpoint inhibitors include inhibitors against immune checkpointmolecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR,CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3 (e.g., INCAGN2385),TIM3 (e.g., INCB2390), VISTA, PD-1, PD-L1 and PD-L2. In someembodiments, the immune checkpoint molecule is a stimulatory checkpointmolecule selected from CD27, CD28, CD40, ICOS, OX40 (e.g., INCAGN1949),GITR (e.g., INCAGN1876) and CD137. In some embodiments, the immunecheckpoint molecule is an inhibitory checkpoint molecule selected fromA2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA.In some embodiments, the compounds provided herein can be used incombination with one or more agents selected from KIR inhibitors, TIGITinhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRbeta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule PD-L1 inhibitor. In some embodiments, the small moleculePD-L1 inhibitor has an IC50 less than 1 μM, less than 100 nM, less than10 nM or less than 1 nM in a PD-L1 assay described in US PatentPublication Nos. US 20170107216, US 20170145025, US 20170174671, US20170174679, US 20170320875, US 20170342060, US 20170362253, and US20180016260, each of which is incorporated by reference in its entiretyfor all purposes.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is MGA012, nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001,ipilumimab or AMP-224. In some embodiments, the anti-PD-1 monoclonalantibody is nivolumab or pembrolizumab. In some embodiments, theanti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD1antibody is nivolumab. In some embodiments, the anti-PD-1 monoclonalantibody is MGA012 (retifanlimab). In some embodiments, the anti-PD1antibody is SHR-1210. Other anti-cancer agent(s) include antibodytherapeutics such as 4-1BB (e.g. urelumab, utomilumab.

In some embodiments, the compounds of the disclosure can be used incombination with INCB086550.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MED14736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MED14736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916,PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40Lfusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD19, e.g., an anti-CD19 antibody. In some embodiments,the anti-CD19 antibody is tafasitamab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors for the treatment of diseases, suchas cancer or infections. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CBL-B, CD20,CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3Kdelta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB),ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7/8), TIGIT,CD112R, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments, the immunecheckpoint molecule is a stimulatory checkpoint molecule selected fromCD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, theimmune checkpoint molecule is an inhibitory checkpoint molecule selectedfrom A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3,TIGIT, and VISTA. In some embodiments, the compounds provided herein canbe used in combination with one or more agents selected from KIRinhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4inhibitors and TGFR beta inhibitors.

In some embodiments, the compounds provided herein can be used incombination with one or more agonists of immune checkpoint molecules,e.g., OX40, CD27, GITR, and CD137 (also known as 4-1BB).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 or PD-L1, e.g., an anti-PD-1 or anti-PD-L1monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1antibody is nivolumab, pembrolizumab, atezolizumab, durvalumab,avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab,spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001),camrelizumab (SHR-1210), sintilimab (IB1308), AB122 (GLS-010), AMP-224,AMP-514/MEDI-0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MED14736,FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316,CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333,MSB-2311, HLX20, TSR-042, or LY3300054. In some embodiments, theinhibitor of PD-1 or PD-L1 is one disclosed in U.S. Pat. Nos. 7,488,802,7,943,743, 8,008,449, 8,168,757, 8,217, 149, or 10,308,644; U.S. Publ.Nos. 2017/0145025, 2017/0174671, 2017/0174679, 2017/0320875,2017/0342060, 2017/0362253, 2018/0016260, 2018/0057486, 2018/0177784,2018/0177870, 2018/0179179, 2018/0179201, 2018/0179202, 2018/0273519,2019/0040082, 2019/0062345, 2019/0071439, 2019/0127467, 2019/0144439,2019/0202824, 2019/0225601, 2019/0300524, or 2019/0345170; or PCT Pub.Nos. WO 03042402, WO 2008156712, WO 2010089411, WO 2010036959, WO2011066342, WO 2011159877, WO 2011082400, or WO 2011161699, which areeach incorporated herein by reference in their entirety. In someembodiments, the inhibitor of PD-L1 is INCB086550.

In some embodiments, the antibody is an anti-PD-1 antibody, e.g., ananti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab,camrelizumab, cetrelimab, toripalimab, sintilimab, AB122, AMP-224,JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042.In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab,cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, orsintilimab. In some embodiments, the anti-PD-1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab.In some embodiments, the anti-PD-1 antibody is cemiplimab. In someembodiments, the anti-PD-1 antibody is spartalizumab. In someembodiments, the anti-PD-1 antibody is camrelizumab. In someembodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments,the anti-PD-1 antibody is toripalimab. In some embodiments, theanti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1antibody is AB122. In some embodiments, the anti-PD-1 antibody isAMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. Insome embodiments, the anti-PD-1 antibody is BGB-108. In someembodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, theanti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1antibody is LZM009. In some embodiments, the anti-PD-1 antibody isAK105. In some embodiments, the anti-PD-1 antibody is HLX10. In someembodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, theanti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In someembodiments, the anti-PD1 antibody is SHR-1210. Other anti-canceragent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab,utomilumab). In some embodiments, the inhibitor of an immune checkpointmolecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonalantibody. In some embodiments, the anti-PD-L1 monoclonal antibody isatezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736,atezolizumab (MPDL3280A; also known as RG7446), avelumab (MSB0010718C),FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301,BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, theanti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, ortislelizumab. In some embodiments, the anti-PD-L1 antibody isatezolizumab. In some embodiments, the anti-PD-L1 antibody is avelumab.In some embodiments, the anti-PD-L1 antibody is durvalumab. In someembodiments, the anti-PD-L1 antibody is tislelizumab. In someembodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments,the anti-PD-L1 antibody is MED14736. In some embodiments, the anti-PD-L1antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody isKN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In someembodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments,the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1antibody is A167. In some embodiments, the anti-PD-L1 antibody isSTI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. Insome embodiments, the anti-PD-L1 antibody is BGB-A333. In someembodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments,the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1antibody is LY3300054.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule that binds to PD-L1, or a pharmaceutically acceptablesalt thereof. In some embodiments, the inhibitor of an immune checkpointmolecule is a small molecule that binds to and internalizes PD-L1, or apharmaceutically acceptable salt thereof. In some embodiments, theinhibitor of an immune checkpoint molecule is a compound selected fromthose in US 2018/0179201, US 2018/0179197, US 2018/0179179, US2018/0179202, US 2018/0177784, US 2018/0177870, U.S. Ser. No. 16/369,654(filed Mar. 29, 2019), and U.S. Ser. No. 62/688,164, or apharmaceutically acceptable salt thereof, each of which is incorporatedherein by reference in its entirety.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4 and TGFR beta.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftilagimodalpha (IMP321).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isoleclumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT isOMP-31M32.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of VISTA. In some embodiments, the inhibitor of VISTA isJNJ-61610588 or CA-170.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 isenoblituzumab, MGD009, or 8H9.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR. In some embodiments, the inhibitor of KIR islirilumab or IPH4102.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of A2aR. In some embodiments, the inhibitor of A2aR isCPI-444.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-betais trabedersen, galusertinib, or M7824.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PI3K-gamma. In some embodiments, the inhibitor ofPI3K-gamma is IPI-549.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD47. In some embodiments, the inhibitor of CD47 isHu5F9-G4 or TTI-621.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isMED19447.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD70. In some embodiments, the inhibitor of CD70 iscusatuzumab or BMS-936561.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7/8, and CD137 (alsoknown as 4-1BB).

In some embodiments, the agonist of CD137 is urelumab. In someembodiments, the agonist of CD137 is utomilumab.

In some embodiments, the agonist of an immune checkpoint molecule is aninhibitor of GITR. In some embodiments, the agonist of GITR is TRX518,MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, orMEDI6469. In some embodiments, the agonist of an immune checkpointmolecule is an agonist of OX40, e.g., OX40 agonist antibody or OX40Lfusion protein. In some embodiments, the anti-OX40 antibody isINCAGN01949, MED10562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998,BMS-986178, or 9B12.. In some embodiments, the OX40L fusion protein isMED16383.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD40. In some embodiments, the agonist of CD40 is CP-870893,ADC-1013, CDX-1140, SEA-CD40, R07009789, JNJ-64457107, APX-005M, or ChiLob 7/4.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of ICOS. In some embodiments, the agonist of ICOS isGSK-3359609, JTX-2011, or MEDI-570.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD28. In some embodiments, the agonist of CD28 istheralizumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of TLR7/8. In some embodiments, the agonist of TLR7/8 isMEDI9197.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor. In some embodiments, the bispecificantibody binds to PD-1 and PD-L1. In some embodiments, the bispecificantibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments,the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments,the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.Inhibitors of arginase inhibitors include INCB1158.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

In some embodiments, the compounds described herein can be used incombination with one or more agents for the treatment of diseases suchas cancer. In some embodiments, the agent is an alkylating agent, aproteasome inhibitor, a corticosteroid, or an immunomodulatory agent.Examples of an alkylating agent include cyclophosphamide (CY), melphalan(MEL), and bendamustine. In some embodiments, the proteasome inhibitoris carfilzomib. In some embodiments, the corticosteroid is dexamethasone(DEX). In some embodiments, the immunomodulatory agent is lenalidomide(LEN) or pomalidomide (POM).

Suitable antiviral agents contemplated for use in combination withcompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Suitable agents for use in combination with compounds described hereinfor the treatment of cancer include chemotherapeutic agents, targetedcancer therapies, immunotherapies or radiation therapy. Compoundsdescribed herein may be effective in combination with anti-hormonalagents for treatment of breast cancer and other tumors. Suitableexamples are anti-estrogen agents including but not limited to tamoxifenand toremifene, aromatase inhibitors including but not limited toletrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds described herein. These include anti-androgens including butnot limited to flutamide, bicalutamide, and nilutamide, luteinizinghormone-releasing hormone (LHRH) analogs including leuprolide,goserelin, triptorelin, and histrelin, LHRH antagonists (e.g.degarelix), androgen receptor blockers (e.g. enzalutamide) and agentsthat inhibit androgen production (e.g. abiraterone).

The compounds described herein may be combined with or in sequence withother agents against membrane receptor kinases especially for patientswho have developed primary or acquired resistance to the targetedtherapy. These therapeutic agents include inhibitors or antibodiesagainst EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 and againstcancer-associated fusion protein kinases such as Bcr-Abl and EML4-Alk.Inhibitors against EGFR include gefitinib and erlotinib, and inhibitorsagainst EGFR/Her2 include but are not limited to dacomitinib, afatinib,lapitinib and neratinib. Antibodies against the EGFR include but are notlimited to cetuximab, panitumumab and necitumumab. Inhibitors of c-Metmay be used in combination with FGFR inhibitors. These includeonartumzumab, tivantnib, and INC-280. Agents against Abl (or Bcr-Abl)include imatinib, dasatinib, nilotinib, and ponatinib and those againstAlk (or EML4-ALK) include crizotinib.

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith FGFR inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR. Antibodies or other therapeutic proteinsagainst VEGF include bevacizumab and aflibercept. Inhibitors of VEGFRkinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib

Activation of intracellular signaling pathways is frequent in cancer,and agents targeting components of these pathways have been combinedwith receptor targeting agents to enhance efficacy and reduceresistance. Examples of agents that may be combined with compoundsdescribed herein include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, andinhibitors of protein chaperones and cell cycle progression.

Agents against the PI3 kinase include but are not limited topilaralisib,idelalisib, buparlisib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus may be combined with FGFR inhibitors. Othersuitable examples include but are not limited to vemurafenib anddabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973(MEK inhibitors). Inhibitors of one or more JAKs (e.g., ruxolitinib,baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), HDACs (e.g., panobinostat), PARP (e.g.,olaparib), and proteasomes (e.g., bortezomib, carfilzomib) can also becombined with compounds described herein. In some embodiments, the JAKinhibitor is selective for JAK1 over JAK2 and JAK3.

Other suitable agents for use in combination with compounds describedherein include chemotherapy combinations such as platinum-based doubletsused in lung cancer and other solid tumors (cisplatin or carboplatinplus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin orcarboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed)or gemcitabine plus paclitaxel bound particles (Abraxane®).

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with compounds describedherein include steroids including 17 alpha-ethinylestradiol,diethylstilbestrol, testosterone, prednisone, fluoxymesterone,methylprednisolone, methyltestosterone, prednisolone, triamcinolone,chlorotrianisene, hydroxyprogesterone, aminoglutethimide, andmedroxyprogesteroneacetate.

Other suitable agents for use in combination with compounds describedherein include: dacarbazine (DTIC), optionally, along with otherchemotherapy drugs such as carmustine (BCNU) and cisplatin; the“Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin andtamoxifen; a combination of cisplatin, vinblastine, and DTIC; ortemozolomide. Compounds described herein may also be combined withimmunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF) in.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-α), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB, PD-L1 and PD-1 antibodies, or antibodies to cytokines(IL-10, TGF-0, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). Non-limiting examples of tumorvaccines that can be used include peptides of melanoma antigens, such aspeptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, ortumor cells transfected to express the cytokine GM-CSF.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, compounds described herein can beadministered in the form of pharmaceutical compositions which refers toa combination of one or more compounds described herein, and at leastone pharmaceutically acceptable carrier or excipient. These compositionscan be prepared in a manner well known in the pharmaceutical art, andcan be administered by a variety of routes, depending upon whether localor systemic treatment is desired and upon the area to be treated.Administration may be topical (including ophthalmic and to mucousmembranes including intranasal, vaginal and rectal delivery), pulmonary(e.g., by inhalation or insufflation of powders or aerosols, includingby nebulizer; intratracheal, intranasal, epidermal and transdermal),ocular, oral or parenteral.

Methods for ocular delivery can include topical administration (eyedrops), subconjunctival, periocular or intravitreal injection orintroduction by balloon catheter or ophthalmic inserts surgically placedin the conjunctival sac. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal, or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, one or more compounds described herein incombination with one or more pharmaceutically acceptable carriers orexcipients. In making the compositions described herein, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders. In some embodiments, the composition issuitable for topical administration.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions described herein can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™) Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from, for example, about 5 mg to about 1000 mg, about 5 mg toabout 100 mg, about 100 mg to about 500 mg or about 10 to about 30 mg,of the active ingredient. In some embodiments, each dosage containsabout 10 mg of the active ingredient. In some embodiments, each dosagecontains about 50 mg of the active ingredient. In some embodiments, eachdosage contains about 25 mg of the active ingredient. The term “unitdosage forms” refers to physically discrete units suitable as unitarydosages for human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 Dg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of one ormore compounds described herein. When referring to these pre-formulationcompositions as homogeneous, the active ingredient is typicallydispersed evenly throughout the composition so that the composition canbe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid pre-formulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, 0.1 to about 500 mg of the active ingredient of thepresent disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds, or compositions as describedherein can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of the compounds in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, compounds of the present disclosure canbe provided in an aqueous physiological buffer solution containing about0.1 to about 10% w/v of the compound for parenteral administration. Sometypical dose ranges are from about 1 μg/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,formulation of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

Compounds described herein can also be formulated in combination withone or more additional active ingredients, which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating FGFR3 protein in tissuesamples, including human, and for identifying FGFR3 ligands byinhibition binding of a labeled compound. Substitution of one or more ofthe atoms of the compounds of the present disclosure can also be usefulin generating differentiated ADME (Adsorption, Distribution, Metabolismand Excretion). Accordingly, the present invention includes FGFR bindingassays that contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula (I) can be optionally substituted with deuterium atoms, suchas —CD₃ being substituted for —CH₃). In some embodiments, alkyl groupsin Formula (I) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. In some embodiments, the compound includes twoor more deuterium atoms. In some embodiments, the compound includes 1-2,1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of thehydrogen atoms in a compound can be replaced or substituted by deuteriumatoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro adenosine receptor labeling andcompetition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹Ior ³⁵S can be useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the invention can be used in a screening assay toidentify and/or evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind an FGFR3 protein by monitoring itsconcentration variation when contacting with the FGFR3, through trackingof the labeling. For example, a test compound (labeled) can be evaluatedfor its ability to reduce binding of another compound which is known tobind to a FGFR3 protein (i.e., standard compound). Accordingly, theability of a test compound to compete with the standard compound forbinding to the FGFR3 protein directly correlates to its bindingaffinity. Conversely, in some other screening assays, the standardcompound is labeled and test compounds are unlabeled. Accordingly, theconcentration of the labeled standard compound is monitored in order toevaluate the competition between the standard compound and the testcompound, and the relative binding affinity of the test compound is thusascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of FGFR-associated diseases ordisorders, such as cancer and other diseases referred to herein whichinclude one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thedisclosure. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof FGFR3 as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass-directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.,“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity analysis under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flowrate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [see“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with the 30×100 mmcolumn was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.15% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 30 mL/minute, the separating gradientwas optimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature [See “PreparativeLCMS Purification: Improved Compound Specific Method Optimization”, K.Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)].Typically, the flow rate used with 30×100 mm column was 60 mL/minute.

Intermediate 1.9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

Step 1. 3-Bromo-5-chloro-1,6-naphthyridine

A flask containing a mixture of phosphoryl chloride (41.4 mL, 444 mmol)and 3-bromo-1,6-naphthyridin-5(6H)-one (5.0 g, 22.2 mmol) was stirred at100° C. for 3 h. The reaction mixture was cooled to room temperature andthe reaction mixture was concentrated in vacuo. The resulting residuewas treated with saturated aqueous NaHCO₃ and the mixture was extractedwith EtOAc. The organic phase was washed with brine, dried over MgSO₄,filtered and the solvent was evaporated in vacuo. The obtained crudeproduct was used in the next step without further purification. LCMScalculated for C₈H₅BrClN₂ (M+H)⁺: m/z=242.9/244.9; found: 243.0/244.9.

Step 2. 3-Bromo-1,6-naphthyridin-5-amine

A mixture of 3-bromo-5-chloro-1,6-naphthyridine (2.68 g, 11.0 mmol),1,4-dioxane (9 mL), and ammonium hydroxide solution (9 mL) in a sealedmicrowave vessel was irradiated at 150° C. for 3 h using a BiotageInitator+ Microwave Synthesizer. The reaction mixture was cooled to roomtemperature and the solvent was evaporated in vacuo. The obtained crudeproduct was used in the next step without further purification. LCMScalculated for C₈H₇BrN₃ (M+H)⁺: m/z=224.0/226.0; found: 224.2/226.2.

Step 3. 9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine

A microwave vessel containing a mixture of3-bromo-1,6-naphthyridin-5-amine (1.32 g, 5.89 mmol), sodium bicarbonate(742 mg, 8.84 mmol), 2-bromo-1-(2,6-dichlorophenyl)ethan-1-one (1.9 g,7.07 mmol) and tert-butanol (8 mL) was irradiated at 150° C. for 9 husing a Biotage Initator+ Microwave Synthesizer. After cooling to roomtemperature, the solid was filtered and washed with CH₂Cl₂, followed byconcentration of the filtrate in vacuo. The resulting residue waspurified by Biotage Isolera to give the desired product as an orangesolid. LCMS calculated for C₁₆H₉BrCl₂N₃ (M+H)⁺: m/z=391.9/393.9/395.9;found: 392.1/394.1/396.1.

Step 4.9-Bromo-2-(2,6-dichlorophenyl)-3-iodoimidazo[2,1-f][1,6]naphthyridine

A vial containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine (200 mg,0.509 mmol), NIS (114 mg, 0.509 mmol) in acetonitrile (2 mL) was stirredat 60° C. for 4 h. The solution was subsequently cooled to roomtemperature, concentrated in vacuo and purified by Biotage Isolera togive the desired product as a brown solid. LCMS calculated forC₁₆H₈BrCl₂IN₃ (M+H)⁺: m/z=517.8/519.8; found: 517.9/519.7.

Step 5. Methyl9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxylate

A mixture of9-bromo-2-(2,6-dichlorophenyl)-3-iodoimidazo[2,1-f][1,6]naphthyridine(1.20 g, 2.31 mmol), triethylamine (967 μL, 6.94 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.267 g, 0.231 mmol) wassuspended in DMF (4.6 mL) and MeOH (4.6 mL). The vial was purged with COgas for 5 min. and then heated to 60° C. for 2 h under an atmosphere ofCO. Upon cooling to room temperature, the solution was quenched withsaturated aqueous NaHCO₃ and extracted into diethyl ether. The combinedorganic layers were dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. The resulting residue was purified by BiotageIsolera to give the desired product as a brown solid. LCMS calculatedfor C₁₈H₁₁BrCl₂N₃O₂ (M+H)⁺: m/z=449.9/451.9; found: 449.9/451.9.

Step 6.9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxylicacid

To a vial containing methyl9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxylate(300 mg, 0.665 mmol) as a suspension in MeOH (1.3 mL) was added 2M aq.sodium hydroxide (665 μL, 1.33 mmol) solution. The reaction was heatedto 50° C. for 1 h. After cooling to room temperature, the pH of themixture was adjusted to ˜5 with saturated aqueous NH₄Cl and acetic acidand then extracted into EtOAc. The combined organic layers were driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo.The resulting residue was purified by Biotage Isolera to give thedesired product as a yellow solid. LCMS calculated for C₁₇H₉BrCl₂N₃O₂(M+H)⁺: m/z=435.9/437.9; found: 435.9/437.9.

Step 7.9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

To a vial containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxylicacid (1.0 g, 2.29 mmol) as a suspension in THF (5 mL) was added SOCl₂(1.0 mL, 13.7 mmol). The vial was heated to 45° C. for 4 h. Aftercooling to room temperature, the reaction mixture was concentrated invacuo and the residue was dissolved in THF (5 mL), cooled to 0° C., andammonium hydroxide solution (800 μL) was added in a dropwise fashionwith stirring. After 10 min, the solution was quenched with saturatedaqueous NaHCO₃ and extracted into EtOAc. The combined organic layerswere dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo. The resulting residue was purified by Biotage Isolera to givethe desired product as a yellow solid. LCMS calculated forC₁₇H₁₀BrCl₂N₄O (M+H)⁺: m/z=434.9/436.9; found: 434.9/436.9.

Example 1.2-(2,6-Dichlorophenyl)-9-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

A vial containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(Intermediate 1, 90 mg, 0.206 mmol),2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol(59 mg, 0.248 mmol), potassium phosphate, tribasic (88 mg, 0.413 mmol),and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)dichloromethane adduct (17 mg, 0.021 mmol) was evacuated and backfilledwith nitrogen three times, followed by the addition of 1,4-dioxane (1.9mL) and water (190 μL). The vial was sealed and heated to 80° C. for 1h. After cooling to room temperature, the mixture was filtered through aSiliaPrep SPE thiol cartridge (SPE-R51030B-06P) and washed withacetonitrile. The mixture was then diluted with acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.10% TFA, at flow rate of 60 mL/min) toprovide the title compound as a TFA salt. LCMS calculated forC₂₂H₁₇Cl₂N₆O₂ (M+H)⁺: m/z=467.1/469.1; found: 467.1/469.1. ¹H NMR (500MHz, DMSO-d₆) δ 9.34 (d, J=2.3 Hz, 1H), 9.25 (d, J=7.7 Hz, 1H), 8.99 (d,J=2.2 Hz, 1H), 8.61 (s, 1H), 8.27 (d, J=0.8 Hz, 1H), 7.72-7.67 (m, 2H),7.60 (dd, J=8.9, 7.3 Hz, 1H), 7.55 (dd, J=7.7, 0.7 Hz, 1H), 4.20 (t,J=5.6 Hz, 2H), 3.81 (t, J=5.6 Hz, 2H).

Example 2.2-(2,6-Dichlorophenyl)-9-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olreplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₄H₂₁Cl₂N₆O₂ (M+H)⁺: m/z=495.1/497.1; found: 495.1/497.1. ¹H NMR (400MHz, DMSO-d₆) δ 9.35 (d, J=2.3 Hz, 1H), 9.25 (d, J=7.7 Hz, 1H), 8.99 (d,J=2.2 Hz, 1H), 8.54 (s, 1H), 8.27 (s, 1H), 7.73-7.65 (m, 2H), 7.60 (dd,J=9.0, 7.1 Hz, 1H), 7.55 (d, J=7.7 Hz, 1H), 4.07 (s, 2H), 1.12 (s, 6H).

Example 3.9-(1-(1-Amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanamidereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₄H₂₀Cl₂N₇O₂ (M+H)⁺: m/z=508.1/510.1; found: 508.1/510.1. ¹H NMR (400MHz, DMSO-d₆) δ 9.41 (d, J=2.3 Hz, 1H), 9.25 (d, J=7.6 Hz, 1H), 9.08 (d,J=2.2 Hz, 1H), 8.81 (s, 1H), 8.33 (s, 1H), 7.73-7.66 (m, 2H), 7.60 (dd,J=9.0, 7.1 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 1.77 (s, 6H).

Example 4.2-(2,6-Dichlorophenyl)-9-(4-(morpholine-4-carbonyl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, withmorpholino(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanonereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₈H₂₂Cl₂N₅O₃ (M+H)⁺: m/z=546.1/548.1; found: 546.0/548.0.

Example 5.2-(2,6-Dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

A flask containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(Intermediate 1, 70 mg, 0.16 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(63 mg, 0.19 mmol), potassium phosphate, tribasic (102 mg, 0.48 mmol),and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (12 mg,0.016 mmol) was evacuated and backfilled with nitrogen three times,followed by the addition of 1,4-dioxane (1 mL) and water (100 μL). Thevial was sealed and heated to 80° C. for 30 min. After cooling to roomtemperature, the mixture was filtered through Celite and washed withCH₂Cl₂, followed by concentration of the filtrate in vacuo. The obtainedcrude product was then dissolved in CH₂Cl₂ (1 mL) and TFA (1 mL) andleft to stir at r.t. for 1 h. The reaction mixture was concentrated invacuo, then redissolved in MeOH (1 mL) and added to a stirring solutionof saturated aqueous NaHCO₃ (5 mL). The resulting precipitate wasfiltered and collected, followed by drying under vacuum. A small amountof the resulting solid (10 mg) was further diluted with acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.10% TFA, at flow rate of 60 mL/min) toprovide the title compound as a TFA salt. LCMS calculated forC₂₀H₁₃Cl₂N₆O (M+H)⁺: m/z=423.1/425.1; found: 423.3/425.3. ¹H NMR (400MHz, DMSO-d₆) δ 9.38 (d, J=2.3 Hz, 1H), 9.25 (d, J=7.7 Hz, 1H), 9.02 (d,J=2.3 Hz, 1H), 8.48 (s, 2H), 7.70 (d, J=1.3 Hz, 1H), 7.68 (s, 1H), 7.60(dd, J=9.1, 7.1 Hz, 1H), 7.55 (d, J=7.7 Hz, 1H).

Example 6.9-(1-(1-Cyanopropan-2-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

To a vial containing a mixture of2-(2,6-dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(Example 5, 15 mg, 0.035 mmol) and cesium carbonate (35 mg, 0.106 mmol)as a solution in DMF (500 μL) was added 3-bromobutanenitrile (6 mg,0.035 mmol). The vial was sealed and heated to 80° C. for 5 h. Aftercooling to room temperature, the mixture was then diluted withacetonitrile and purified with prep-LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.10% TFA, at flow rateof 60 mL/min) to provide the title compound as a TFA salt. LCMScalculated for C₂₄H₁₈Cl₂N₇O (M+H)⁺: m/z=490.1/492.1; found: 490.1/492.0.

Example 7.2-(2,6-Dichlorophenyl)-9-(1-(2-hydroxybutyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 6, with 1-bromobutan-2-ol replacing 3-bromobutanenitrile toprovide the title compound as a TFA salt. LCMS calculated forC₂₄H₂₁Cl₂N₆O₂ (M+H)⁺: m/z=495.1/497.1; found: 495.1/497.0. ¹H NMR (400MHz, DMSO-d₆) δ 9.34 (d, J=2.3 Hz, 1H), 9.24 (d, J=7.7 Hz, 1H), 8.98 (d,J=2.3 Hz, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 7.70 (d, J=1.3 Hz, 1H), 7.68(s, 1H), 7.60 (dd, J=9.0, 7.1 Hz, 1H), 7.55 (d, J=7.7 Hz, 1H), 4.23-3.96(m, 2H), 3.86-3.74 (m, 1H), 1.60-1.22 (m, 2H), 0.92 (t, J=7.4 Hz, 3H).

Example 8.2-(2,6-Dichlorophenyl)-9-(1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 6, with 4-(bromomethyl)-4-fluorotetrahydro-2H-pyran replacing3-bromobutanenitrile to provide the title compound as a TFA salt. LCMScalculated for C₂₆H₂₂Cl₂FN₆O₂ (M+H)⁺: m/z=539.1/541.1; found:539.2/541.2.

Example 9.9-(1-((5-Cyanopyridin-3-yl)methyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

To a vial containing a mixture of2-(2,6-dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(10 mg, 0.024 mmol) and cesium carbonate (23 mg, 0.071 mmol) as asolution in DMF (500 μL) was added 5-(bromomethyl)nicotinonitrile (7 mg,0.035 mmol). The reaction mixture was left to stir at room temperaturefor 1 h. The mixture was then diluted with TFA and acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the title compound as a TFA salt. LCMS calculated forC₂₇H₁₇Cl₂N₈O (M+H)⁺: m/z=539.1/541.1; found: 539.0/541.0.

Example 10.9-(1-((2-Cyanopyridin-4-yl)methyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 9, with 4-(bromomethyl)picolinonitrile replacing5-(bromomethyl)nicotinonitrile to provide the title compound as a TFAsalt. LCMS calculated for C₂₇H₁₇Cl₂N₈O (M+H)⁺: m/z=539.1/541.1; found:539.0/541.0.

Example 11.2-(2,6-Dichlorophenyl)-9-(1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

To a vial containing a mixture of2-(2,6-dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(10 mg, 0.024 mmol) and cesium carbonate (23 mg, 0.071 mmol) as asolution in acetonitrile (500 μL) was added 4-(bromomethyl)pyrimidinehydrobromide (9 mg, 0.035 mmol). The vial was sealed and heated to 50°C. for 2 h. After cooling to room temperature, the mixture was thendiluted with acetonitrile and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min) to provide the title compound as a TFAsalt. LCMS calculated for C₂₅H₁₇Cl₂N₈O (M+H)⁺: m/z=515.1/517.1; found:515.0/517.0.

Example 12.9-(1-(1-(2-Cyanopyridin-4-yl)ethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

Step 1. 4-(1-Hydroxyethyl)picolinonitrile

To a vial containing 4-acetylpicolinonitrile (151 mg, 1.03 mmol) as asolution in methanol (6.5 mL) at 0° C. was added sodium borohydride (78mg, 2.07 mmol) in one portion. The reaction mixture was warmed to roomtemperature and left to stir for 30 min. The reaction was then quenchedwith dropwise addition of water (2 mL) and was extracted with CH₂Cl₂(3×). The combined organics were dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo. The obtained crude product was usedin the next step without further purification. LCMS calculated forC₈H₉N₂O (M+H)⁺: m/z=149.1; found: 149.0.

Step 2. 1-(2-Cyanopyridin-4-yl)ethyl methanesulfonate

To a vial containing 4-(1-hydroxyethyl)picolinonitrile (110 mg, 0.74mmol) as a solution in CH₂Cl₂ (7.4 mL) was added triethylamine (310 μL,2.23 mmol) and left to stir for 1 min before adding methanesulfonylchloride (75 μL, 0.965 mmol). The reaction mixture was left to stir atroom temperature for 1 h before all volatiles were concentrated invacuo. The resulting crude residue was diluted with CH₂Cl₂ (3 mL) andsaturated aqueous NaHCO₃ (3 mL), then extracted with CH₂Cl₂ (3×). Thecombined organics were dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. The obtained crude product was used in thenext step without further purification. LCMS calculated for C₉H₁₁N₂O₃S(M+H)⁺: m/z=227.0; found: 227.1.

Step 3.9-(1-(1-(2-Cyanopyridin-4-yl)ethyl)-H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 9, with 1-(2-cyanopyridin-4-yl)ethyl methanesulfonate replacing5-(bromomethyl)nicotinonitrile to provide the title compound as a TFAsalt. LCMS calculated for C₂₈H₁₉Cl₂N₈O (M+H)⁺: m/z=553.1/555.1; found:553.0/555.0.

Example 13.2-(2,6-Dichlorophenyl)-9-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

Step 1. 4-(4-Bromophenyl)-3,6-dihydro-2H-thiopyran

A vial containing 1-bromo-4-iodobenzene (1.0 g, 3.53 mmol),2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(839 mg, 3.71 mmol), potassium carbonate (1.47 g, 10.6 mmol), and(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (289 mg,0.353 mmol) was evacuated and backfilled with nitrogen three times,followed by the addition of 1,4-dioxane (10.6 mL) and water (5.3 mL).The vial was sealed and heated to 80° C. for 1 h. After cooling to roomtemperature, the mixture was filtered through Celite and washed withCH₂Cl₂, followed by concentration of the filtrate in vacuo. Theresulting residue was purified by Biotage Isolera to give the desiredproduct. LCMS calculated for the corresponding sulfoxide C₁₁H₁₂BrOS:m/z=271.0/273.0; found: 270.9/273.0.

Step 2. 4-(4-Bromophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide

To a vial containing 4-(4-bromophenyl)-3,6-dihydro-2H-thiopyran (580 mg,2.27 mmol) as a solution in CH₂Cl₂ (3.5 mL) at 0° C. was added m-CPBA(77 wt %, 1.0 g, 4.55 mmol) as a solution in CH₂Cl₂ (3.5 mL). Thereaction mixture was left to stir for 30 min before being quenched withsaturated aqueous NaHCO₃ (5 mL) and was extracted with CH₂Cl₂ (3×). Thecombined organics were washed with brine, then dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. The resultingresidue was purified by Biotage Isolera to give the desired product.LCMS calculated for the corresponding hydrate C₁₁H₁₁BrO₂S.H₂O:m/z=304.0/306.0; found: 304.0/306.0.

Step 3. 4-(4-Bromophenyl)tetrahydro-2H-thiopyran 1,1-dioxide

To a Parr vessel containing 4-(4-bromophenyl)-3,6-dihydro-2H-thiopyran1,1-dioxide (346 mg, 1.20 mmol) as a suspension in EtOAc (12 mL) wasadded platinum(IV) oxide (27 mg, 0.12 mmol). A Parr apparatus wasoutfitted with the vessel, which was then evacuated and backfilled withnitrogen three times, followed by one more evacuation and pressurizationwith hydrogen to 45 psi. The Parr vessel was then shaken for 16 h atroom temperature. Upon completion, the reaction mixture was filteredover Celite, washing with MeOH and concentrated in vacuo. The obtainedcrude product was used in the next step without further purification.LCMS calculated for the corresponding hydrate C₁₁H₁₃BrO₂S.H₂O:m/z=306.0/308.0; found: 306.0/308.0.

Step 4.4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-thiopyran1,1-dioxide

A vial containing 4-(4-bromophenyl)tetrahydro-2H-thiopyran 1,1-dioxide(50 mg, 0.173 mmol), bis(pinacolato)diboron (66 mg, 0.259 mmol),potassium acetate (34 mg, 0.346 mmol), and(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)dichloromethane adduct (14 mg, 0.017 mmol) was evacuated and backfilledwith nitrogen three times, followed by the addition of 1,4-dioxane (1.1mL). The vial was sealed and heated to 80° C. for 16 h. After cooling toroom temperature, the mixture was filtered through Celite, washed withTHF (5 mL) followed by concentration of the filtrate in vacuo. Theobtained crude product was used in the next step without furtherpurification. LCMS calculated for the corresponding hydrateC₁₇H₂₅BO₄S.H₂O: m/z=354.2; found: 354.2.

Step 5.2-(2,6-Dichlorophenyl)-9-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

A vial containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(10 mg, 0.023 mmol),4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-thiopyran1,1-dioxide (12 mg, 0.034 mmol), potassium phosphate, tribasic (15 mg,0.069 mmol), and(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (3 mg, 3.44μmol) was evacuated and backfilled with nitrogen three times, followedby the addition of 1,4-dioxane (1 mL) and water (250 μL). The vial wassealed and heated to 80° C. for 30 min. After cooling to roomtemperature, the mixture was filtered through Celite and washed withCH₂Cl₂, followed by concentration of the filtrate in vacuo. The residuewas then dissolved with acetonitrile and purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.10% TFA, at flow rate of 60 mL/min) to provide the titlecompound as a TFA salt. LCMS calculated for C₂₈H₂₃Cl₂N₄O₃S (M+H)⁺:m/z=565.1/567.1; found: 565.2/567.2.

Example 14.2-(2,6-Dichlorophenyl)-9-(4-(1,1-dioxidothiomorpholino)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 13, starting from Step 4, with 4-(4-bromophenyl)thiomorpholine1,1-dioxide replacing 4-(4-bromophenyl)tetrahydro-2H-thiopyran1,1-dioxide to provide the title compound as a TFA salt. LCMS calculatedfor C₂₇H₂₂Cl₂N₅O₃S (M+H)⁺: m/z=566.1/568.1; found: 566.2/568.2.

Example 15.2-(2,6-Dichlorophenyl)-9-(1-(pyrimidin-2-ylmethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 9, with 2-(chloromethyl)pyrimidine replacing5-(bromomethyl)nicotinonitrile to provide the title compound as a TFAsalt. LCMS calculated for C₂₅H₁₇Cl₂N₈O (M+H)⁺: m/z=515.1/517.1; found:515.2/517.2.

Example 16.9-(1-((6-Cyanopyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 9, with 6-(bromomethyl)picolinonitrile replacing5-(bromomethyl)nicotinonitrile to provide the title compound as a TFAsalt. LCMS calculated for C₂₇H₁₇Cl₂N₈O (M+H)⁺: m/z=539.1/541.1; found:539.2/541.2. ¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (d, J=2.2 Hz, 1H), 9.25(d, J=7.7 Hz, 1H), 9.03 (d, J=2.3 Hz, 1H), 8.80 (s, 1H), 8.38 (s, 1H),8.08 (t, J=7.8 Hz, 1H), 8.01 (dd, J=7.7, 1.1 Hz, 1H), 7.72-7.66 (m, 2H),7.60 (dd, J=9.1, 7.1 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.53 (dd, J=8.0,1.1 Hz, 1H), 5.58 (s, 2H).

Example 17.9-(4-(4-Acetylpiperazin-1-yl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

Step 1.2-(2,6-Dichlorophenyl)-9-(4-(piperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

A flask containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(Intermediate 1, 40 mg, 0.092 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(39 mg, 0.10 mmol), potassium phosphate, tribasic (58 mg, 0.27 mmol),and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (7 mg,9.2 μmol) was evacuated and backfilled with nitrogen three times,followed by the addition of 1,4-dioxane (1 mL) and water (250 μL). Thevial was sealed and heated to 80° C. for 30 min. After cooling to roomtemperature, the mixture was filtered through Celite and washed withCH₂Cl₂, followed by concentration of the filtrate in vacuo. The obtainedcrude product was then dissolved in CH₂Cl₂ (1 mL) and TFA (1 mL) andleft to stir at r.t. for 1 h. The reaction mixture was concentrated invacuo, then redissolved in MeOH (1 mL) and added to a stirring solutionof saturated aqueous NaHCO₃ (5 mL). The resulting precipitate wasfiltered and collected, followed by drying under vacuum. The obtainedcrude product was used in the next step without further purification.LCMS calculated for C₂₇H₂₃Cl₂N₆O (M+H)⁺: m/z=517.1/519.1; found:517.3/519.3.

Step 2.9-(4-(4-Acetylpiperazin-1-yl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

To a vial containing2-(2,6-dichlorophenyl)-9-(4-(piperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(12 mg, 0.023 mmol) as a solution in DMF (500 μL) was added DIPEA (8 μL,0.045 mmol) and acetic acid (2 μL, 0.035 mmol), followed by HATU (13 mg,0.035 mmol). The reaction mixture was left to stir at r.t. for 1 h, uponwhich time water was added and the resulting solid was collected byfiltration and washed with water. The solid was then dissolved with TFAand purified with prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.10% TFA, at flow rate of 60 mL/min)to provide the title compound as a TFA salt. LCMS calculated forC₂₉H₂₅Cl₂N₆O₂ (M+H)⁺: m/z=559.1/561.1; found: 559.1/561.3.

Example 18.2-(2,6-Dichlorophenyl)-9-(4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 17, with 2-hydroxyacetic acid replacing acetic acid in Step 2 toprovide the title compound as a TFA salt. LCMS calculated forC₂₉H₂₅Cl₂N₆O₃ (M+H)⁺: m/z=575.1/577.1; found: 575.0/577.0.

Example 19.9-(4-((4-Acetylpiperazin-1-yl)methyl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

Step 1.2-(2,6-Dichlorophenyl)-9-(4-(piperazin-1-ylmethyl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

A vial containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(Intermediate 1, 20 mg, 0.046 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine-1-carboxylate(20 mg, 0.05 mmol), potassium phosphate, tribasic (29 mg, 0.14 mmol),and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (4 mg,4.6 μmol) was evacuated and backfilled with nitrogen three times,followed by the addition of 1,4-dioxane (1 mL) and water (250 μL). Thevial was sealed and heated to 80° C. for 30 min. After cooling to roomtemperature, the mixture was filtered through Celite and washed withCH₂Cl₂, followed by concentration of the filtrate in vacuo. The obtainedcrude product was then dissolved in CH₂Cl₂ (1 mL) and TFA (1 mL) andleft to stir at r.t. for 1 h. The reaction mixture was concentrated invacuo, then redissolved in MeOH (1 mL) and added to a stirring solutionof saturated aqueous NaHCO₃ (5 mL). The resulting precipitate wasfiltered and collected, followed by drying under vacuum. The obtainedcrude product was used in the next step without further purification.LCMS calculated for C₂₈H₂₅Cl₂N₆O (M+H)⁺: m/z=531.1/533.1; found:531.3/533.3.

Step 2.9-(4-((4-Acetylpiperazin-1-yl)methyl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

To a vial containing2-(2,6-dichlorophenyl)-9-(4-(piperazin-1-ylmethyl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(12 mg, 0.023 mmol) as a solution in DMF (500 μL) was added DIPEA (8 μL,0.045 mmol) and acetic acid (2 μL, 0.035 mmol), followed by HATU (13 mg,0.035 mmol). The reaction mixture was left to stir at r.t. for 1 h, uponwhich time water was added and the resulting solid was collected byfiltration and washed with water.

The solid was then dissolved with TFA and purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.10% TFA, at flow rate of 60 mL/min) to provide the titlecompound as a TFA salt. LCMS calculated for C₃₀H₂₇Cl₂N₆O₂ (M+H)⁺:m/z=573.2/575.2; found: 573.1/575.1.

Example 20.2-(2,6-Dichlorophenyl)-9-(4-((4-(2-hydroxyacetyl)piperazin-1-yl)methyl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 19, with 2-hydroxyacetic acid replacing acetic acid in Step 2 toprovide the title compound as a TFA salt. LCMS calculated forC₃₀H₂₇Cl₂N₆O₃ (M+H)⁺: m/z=589.2/591.1; found: 589.1/591.0.

Example 21.2-(2,6-Dichlorophenyl)-9-(4-(4-methylpiperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

To a vial containing2-(2,6-dichlorophenyl)-9-(4-(piperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(12 mg, 0.023 mmol) as a solution in CH₂Cl₂ (1 mL) was added acetic acid(4 μL, 0.07 mmol) and aqueous formaldehyde solution (37 wt %, 17 μL,0.23 mmol), followed by sodium triacetoxyborohydride (10 mg, 0.046 mmol)and left to stir at r.t. for 1 h. The reaction mixture was concentratedin vacuo and the crude residue was dissolved in acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.10% TFA, at flow rate of 60 mL/min) toprovide the title compound as a TFA salt. LCMS calculated forC₂₈H₂₅Cl₂N₆O (M+H)⁺: m/z=531.2/533.1; found: 531.0/533.0. ¹H NMR (400MHz, DMSO-d₆) δ 9.38 (d, J=2.4 Hz, 1H), 9.29 (d, J=7.7 Hz, 1H), 8.98 (d,J=2.4 Hz, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.73-7.66 (m, 2H), 7.65-7.51 (m,2H), 7.18 (d, J=8.9 Hz, 2H), 4.02 (d, J=13.2 Hz, 2H), 3.55 (d, J=12.0Hz, 2H), 3.25-3.12 (m, 2H), 3.06 (t, J=12.5 Hz, 2H), 2.89 (s, 3H).

Example 22.9-(4-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

Step 1.4-(3-Carbamoyl-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)benzoicacid

A vial containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(Intermediate 1, 20 mg, 0.046 mmol),(4-(tert-butoxycarbonyl)phenyl)boronic acid (11 mg, 0.05 mmol),potassium phosphate, tribasic (29 mg, 0.138 mmol), and(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (4 mg, 4.6μmol) was evacuated and backfilled with nitrogen three times, followedby the addition of 1,4-dioxane (1 mL) and water (250 μL). The vial wassealed and heated to 80° C. for 30 min. After cooling to roomtemperature, the mixture was filtered through Celite and washed withCH₂Cl₂, followed by concentration of the filtrate in vacuo. The cruderesidue was then dissolved in CH₂Cl₂ (1 mL) and TFA (1 mL) and left tostir at r.t. for 1 h. The reaction mixture was concentrated in vacuo,then dissolved in MeOH (1 mL) and added to a stirring solution ofsaturated aqueous NaHCO₃ (10 mL). The resulting precipitate was filteredand collected, followed by drying under vacuum. The obtained crudeproduct was used in the next step without further purification. LCMScalculated C₂₄H₁₅Cl₂N₄O₃ (M+H)⁺: m/z=477.1/479.0; found: 477.2/479.2.

Step 2.9-(4-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

To a vial containing4-(3-carbamoyl-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)benzoicacid (15 mg, 0.031 mmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptanehydrochloride (6 mg, 0.047 mmol), DMF (500 μL) and DIPEA (22 μL, 0.126mmol) was added HATU (18 mg, 0.047 mmol). The reaction mixture was leftto stir at r.t. for 1 h, upon which time water was added and theresulting solid was collected by filtration and washed with water. Thesolid was then dissolved with TFA and purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to provide the title compound as aTFA salt. LCMS calculated for C₂₉H₂₂Cl₂N₅O₃ (M+H)⁺: m/z=558.1/560.1;found: 558.3/560.3.

Example 23.9-(1-(Cyanomethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrilereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₂H₁₄Cl₂N₇O (M+H)⁺: m/z=462.1/464.1; found: 462.1/464.1.

Example 24.2-(2,6-Dichlorophenyl)-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₅H₂₁Cl₂N₆O₂ (M+H)⁺: m/z=507.1/509.1; found: 507.1/509.1.

Example 25.9-(1-Benzyl-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1,1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₇H₁₉Cl₂N₆O (M+H)⁺: m/z=513.1/515.1; found: 513.2/515.1.

Example 26.2-(2,6-Dichlorophenyl)-9-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with1-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₃H₁₉Cl₂N₆O₃S (M+H)⁺: m/z=529.1/531.1; found: 529.1/531.1.

Example 27.9-(1-(1-Cyanoethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrilereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₃H₁₆Cl₂N₇O (M+H)⁺: m/z=476.1/478.1; found: 476.0/478.0.

Example 28.2-(2,6-Dichlorophenyl)-9-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₂H₁₅Cl₂F₂N₆O (M+H)⁺: m/z=487.1/489.1; found: 487.0/489.0.

Example 29.2-(2,6-Dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidinereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₆H₂₄Cl₂N₇O (M+H)⁺: m/z=520.1/522.1; found: 520.1/522.1.

Example 30.2-(2,6-Dichlorophenyl)-9-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-olreplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₄H₂₁Cl₂N₆O₂ (M+H)⁺: m/z=495.1/497.1; found: 495.1/497.1.

Example 31.9-(1-(2-Cyanopropan-2-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrilereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₄H₁₈Cl₂N₇O (M+H)⁺: m/z 10=490.1/492.1; found: 490.1/492.1.

Example 32.9-(1-Cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₃H₁₇Cl₂N₆O (M+H)⁺: m/z=463.1/465.1; found: 463.2/465.2.

Example 33.2-(2,6-Dichlorophenyl)-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₂H₁₄Cl₂F₃N₆O (M+H)⁺: m/z=505.1/507.1; found: 505.2/507.2.

Example 34.2-(2,6-Dichlorophenyl)-9-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, withN,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-aminereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₄H₂₂Cl₂N₇O (M+H)⁺: m/z=494.1/496.1; found: 494.0/496.0.

Example 35.2-(2,6-Dichlorophenyl)-9-(1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with1-(1-methoxy-2-methylpropan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₅H₂₃Cl₂N₆O₂ (M+H)⁺: m/z=509.1/511.1; found: 509.1/511.1.

Example 36.2-(2,6-Dichlorophenyl)-9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olreplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₃H₁₉Cl₂N₆O₂ (M+H)⁺: m/z=481.1/483.1; found: 481.1/483.1.

Example 37.2-(2,6-Dichlorophenyl)-9-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, withN,N-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-aminereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₅H₂₄Cl₂N₇O (M+H)⁺: m/z=508.1/510.1; found: 508.1/510.1.

Example 38.2-(2,6-Dichlorophenyl)-9-(1-methyl-1H-imidazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazolereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₁H₁₅Cl₂N₆O (M+H)⁺: m/z=437.1/439.1; found: 436.9/438.9.

Example 39.2-(2,6-Dichlorophenyl)-9-(6-oxo-1,6-dihydropyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₂H₁₄Cl₂N₅O₂ (M+H)⁺: m/z=450.1/452.0; found: 450.0/452.0.

Example 40.2-(2,6-Dichlorophenyl)-9-(5-isopropyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with5-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₃H₁₉Cl₂N₆O (M+H)⁺: m/z=465.1/467.1; found: 465.1/467.1.

Example 41.2-(2,6-Dichlorophenyl)-9-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₃H₁₇Cl₂N₆O (M+H)⁺: m/z=463.1/465.1; found: 463.1/465.1.

Example 42.2-(2,6-Dichlorophenyl)-9-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)propan-2-olreplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₅H₂₀Cl₂N₅O₂ (M+H)⁺: m/z=492.1/494.1; found: 492.1/494.1.

Example 43.2-(2,6-Dichlorophenyl)-9-(2-(methylamino)pyrimidin-5-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, withN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-aminereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₂H₁₆Cl₂N₇O (M+H)⁺: m/z=464.1/466.1; found: 464.1/466.1.

Example 44.2-(2,6-Dichlorophenyl)-9-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₄H₁₉Cl₂N₆O₂ (M+H)⁺: m/z=493.1/495.1; found: 493.0/495.0.

Example 45.2-(2,6-Dichlorophenyl)-9-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholinereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₆H₂₄Cl₂N₇O₂ (M+H)⁺: m/z=536.1/538.1; found: 536.0/538.0.

Example 46.2-(2,6-Dichlorophenyl)-9-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with1-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)piperazinereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₇H₂₇Cl₂N₈O (M+H)⁺: m/z=549.2/551.2; found: 549.1/551.1.

Example 47.2-(2,6-Dichlorophenyl)-9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-olreplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₃H₁₉Cl₂N₆O₂ (M+H)⁺: m/z=481.1/483.1; found: 481.1/483.1.

Example 48.9-(1-(2-Cyanoethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrilereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₃H₁₆Cl₂N₇O (M+H)⁺: m/z=476.1/478.1; found: 476.1/478.1.

Example 49.9-(1-(2-Amino-2-oxoethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamidereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₂H₁₆Cl₂N₇O₂ (M+H)⁺: m/z=480.1/482.1; found: 480.1/482.1.

Example 50.2-(2,6-Dichlorophenyl)-9-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propan-2-olreplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₅H₂₀Cl₂N₅O₂ (M+H)⁺: m/z=492.1/494.1; found: 492.1/494.1.

Example 51.2-(2,6-Dichlorophenyl)-9-(6-(2,2,2-trifluoroethyl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)pyridinereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₄H₁₅Cl₂F₃N₅O (M+H)⁺: m/z=516.1/518.1; found: 516.0/518.0.

Example 52.2-(2,6-Dichlorophenyl)-9-(6-(methylcarbamoyl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, withN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamidereplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₄H₁₇Cl₂N₆O₂ (M+H)⁺: m/z=491.1/493.1; found: 491.0/493.0.

Example 53.2-(2,6-Dichlorophenyl)-9-(4-hydroxycyclohex-1-en-1-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

This compound was prepared according to the procedure described inExample 1, with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-olreplacing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olto provide the title compound as a TFA salt. LCMS calculated forC₂₃H₁₉Cl₂N₄O₂ (M+H)⁺: m/z=453.1/455.1; found: 453.1/455.0.

Example 54.2-(2,6-Dichlorophenyl)-9-(5-hydroxypent-1-yn-1-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

A vial containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(Intermediate 1, 8 mg, 0.018 mmol), copper(I) iodide (0.2 mg, 1 μmol)and bis(triphenylphosphine)palladium(II) dichloride (1 mg, 1.8 μmol) wasevacuated and backfilled with nitrogen three times, followed by theaddition of THF (183 μL), triethylamine (13 μL, 0.092 mmol) andpent-4-yn-1-ol (5 μL, 0.055 mmol). The vial was sealed and heated to 55°C. for 2 h. After cooling to room temperature, the mixture was filteredthrough a SiliaPrep SPE thiol cartridge (SPE-R51030B-06P) and washedwith acetonitrile. The mixture was then diluted with acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the title compound as a TFA salt. LCMS calculated forC₂₂H₁₇Cl₂N₄O₂ (M+H)⁺: m/z=439.1/441.1; found: 439.1/441.1.

Example 55.2-(2,6-Dichlorophenyl)-9-(2-hydroxypropan-2-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

To a vial containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(16 mg, 0.037 mmol) as a solution in THF (370 μL) at −78° C. was addedtert-butyllithium (1.7 M in pentane, 43 μL, 0.073 mmol). The reactionmixture was stirred at −78° C. for 5 min before being quenched withacetone (100 μL) followed by diluting with water and was extracted withEtOAc (3×). The combined organics were dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. The resulting residue wasdissolved in acetonitrile and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.10%TFA, at flow rate of 60 mL/min) to provide the title compound as a TFAsalt. LCMS calculated for C₂₀H₁₇Cl₂N₄O₂ (M+H)⁺: m/z=415.1/417.1; found:415.1/417.1.

Example 56.2-(2,6-Dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

To a vial containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide(16 mg, 0.037 mmol) as a solution in THF (370 μL) at −78° C. was addedtert-butyllithium (1.7 M in pentane, 43 μl, 0.073 mmol). The reactionmixture was stirred at −78° C. for 5 min before being quenched withsaturated aqueous NH₄Cl solution (100 μL) and was extracted with EtOAc(3×). The combined organics were dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo. The resulting residue was dissolvedin acetonitrile and purified with prep-LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min) to provide the title compound as a TFA salt. LCMScalculated for C₁₇H₁₁Cl₂N₄O (M+H)⁺: m/z=357.0/359.0; found: 357.0/359.1.

Example 57.2-Methyl-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

Step 1. 9-Bromo-2-chloroimidazo[2,1-f][1,6]naphthyridine

A solution of 3-bromo-1,6-naphthyridin-5-amine (Intermediate 1, Step 2,300 mg, 1.34 mmol), in ethyl bromoacetate (3 mL, 27.1 mmol) was stirredat 60° C. for 3 h. This solution was then cooled to room temperature andthe resulting solid was filtered and washed with CH₂Cl₂. The solid wasthen dissolved in phosphoryl chloride (3 mL, 32.2 mmol) and heated to100° C. for 3 h. Upon completion, the volatiles were removed in vacuoand the crude residue was dissolved in CH₂Cl₂ and washed with saturatedaqueous NaHCO₃. The combined organic layers were dried over anhydroussodium sulfate, and concentrated in vacuo. The obtained crude productwas used in the next step without further purification. LCMS calculatedfor C₁₀H₆BrClN₃ (M+H)⁺: m/z=281.9/283.9; found: 282.1/284.0.

Step 2. 9-Bromo-2-chloro-3-iodoimidazo[2,1-f][1,6]naphthyridine

To a vial containing 9-bromo-2-chloroimidazo[2,1-f][1,6]naphthyridine(400 mg, 1.42 mmol) as a solution in acetonitrile (3 mL) was added NIS(382 mg, 1.7 mmol) and subsequently warmed to 50° C. for 30 min. Uponcompletion, the reaction mixture was cooled to 0° C. and water (1 mL)was added. The resulting solid was collected by filtration, washed withhexanes, and dried under vacuum before taking on directly to the nextstep without further purification. LCMS calculated for C₁₀H₅BrClN₃(M+H)⁺: m/z=407.8/409.8; found: 407.7/409.8.

Step 3. Methyl9-bromo-2-chloroimidazo[2,1-f][1,6]naphthyridine-3-carboxylate

A vial containing9-bromo-2-chloro-3-iodoimidazo[2,1-f][1,6]naphthyridine (200 mg, 0.490mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (18mg, 0.024 mmol) was evacuated and backfilled with a balloon of COfollowed by the addition of DMF (1 mL), MeOH (1 mL), and triethylamine(205 μL, 1.47 mmol). The reaction mixture was heated to 70° C. underatmospheric pressure of CO for 3 h. Upon completion, the reactionmixture was cooled to 0° C. and water (1 mL) was added. The resultingsolid was collected by filtration, washed with hexanes, and dried undervacuum before taking on directly to the next step without furtherpurification. LCMS calculated for C₁₂H₈BrClN₃O₂ (M+H)⁺: m/z=339.9/341.9;found: 339.9/341.9.

Step 4. Methyl2-chloro-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxylate

A vial containing methyl9-bromo-2-chloroimidazo[2,1-f][1,6]naphthyridine-3-carboxylate (200 mg,0.587 mmol),1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(196 mg, 0.705 mmol), potassium phosphate, tribasic (374 mg, 1.76 mmol),and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (43 mg,0.059 mmol) was evacuated and backfilled with nitrogen three times,followed by the addition of 1,4-dioxane (3 mL) and water (300 μL). Thevial was sealed and heated to 80° C. for 30 min. After cooling to roomtemperature, the mixture was diluted with CH₂Cl₂, filtered throughCelite and concentrated in vacuo. The obtained crude product was used inthe next step without further purification. LCMS calculated forC₂₀H₁₉ClN₅O₃ (M+H)⁺: m/z=412.1/414.1; found: 412.3/414.3.

Step 5. Methyl2-methyl-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxylate

A vial containing methyl2-chloro-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-J][1,6]naphthyridine-3-carboxylate(100 mg, 0.243 mmol), trimethylboroxine (41 μL, 0.291 mmol), potassiumphosphate, tribasic (155 mg, 0.73 mmol), and XPhos Pd G2 (19 mg, 0.024mmol) was evacuated and backfilled with nitrogen three times, followedby the addition of 1,4-dioxane (1 mL) and water (100 μL). The vial wassealed and heated to 100° C. for 20 min. After cooling to roomtemperature, the mixture was diluted with CH₂Cl₂, filtered throughCelite and concentrated in vacuo. The obtained crude product was used inthe next step without further purification. LCMS calculated forC₂₁H₂₂N₅O₃ (M+H)⁺: m/z=392.2; found: 392.2.

Step 6.2-Methyl-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

To a vial containing methyl2-methyl-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxylate(50 mg, 0.128 mmol) and LiOH (31 mg, 1.277 mmol) was added THF (600 μL)and water (2 mL). The reaction mixture was stirred at 60° C. for 1 hand, upon completion, excess water was added and the resultingprecipitate was filtered off. The pH of the filtrate was then adjustedto ˜5 with 1N HCl and the resulting precipitate was collected byfiltration and dried under vacuum. The crude solid was then dissolved inTHF (500 μL) followed by the addition of thionyl chloride (48 μL, 0.662mmol) and 1 drop of DMF. The resulting suspension was warmed to 45° C.for 2 h and, upon completion, the volatiles were removed in vacuo. Thecrude residue was dissolved in THF (500 μL) and an ammonium hydroxidesolution (200 μL, 5.14 mmol) was added. The reaction mixture was stirredat room temperature for 5 min at which point the solution was dilutedwith acetonitrile and aqueous TFA then purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to provide the title compound as aTFA salt. LCMS calculated for C₂₀H₂₁N₆O₂ (M+H)⁺: m/z=377.2; found 377.2.

Example 58.9-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

Step 1. 9-Bromoimidazo[2,1-f][1,6]naphthyridine

To a vial containing 3-bromo-1,6-naphthyridin-5-amine (1.0 g, 4.46 mmol)was added sodium bicarbonate (750 mg, 8.93 mmol), ethanol (18 mL) andchloro acetaldehyde (50% in H₂O, 1.1 mL, 8.93 mmol). The vial was sealedand heated to 80° C. for 2 h. Upon completion the reaction was cooled toroom temperature and the solvent was removed in vacuo. The remainingresidue was diluted with CH₂Cl₂, filtered through Celite andconcentrated in vacuo. The obtained crude product was used in the nextstep without further purification.

LCMS calculated for C₁₀H₇BrN₃ (M+H)⁺: m/z=248.0/250.0; found:248.0/250.0.

Step 2. 9-Bromo-3-iodoimidazo[2,1-f][1,6]naphthyridine

To a vial containing 9-bromoimidazo[2,1-f][1,6]naphthyridine (500 mg,2.02 mmol) as a solution in acetonitrile (20 mL) was added NIS (544 mg,2.42 mmol) and subsequently warmed to 50° C. for 1 h. Upon completion,the reaction mixture was cooled to 0° C. The resulting solid wascollected by filtration, washed with cold acetonitrile, and dried undervacuum before taking on directly to the next step without furtherpurification. LCMS calculated for C₁₀H₆BrIN₃ (M+H)⁺: m/z=373.9/375.9;found: 373.8/375.8.

Step 3. Methyl 9-bromoimidazo[2,1-f][1,6]naphthyridine-3-carboxylate

A vial containing 9-bromo-3-iodoimidazo[2,1-f][1,6]naphthyridine (700mg, 1.88 mmol) and1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (69 mg, 0.09mmol) was evacuated and backfilled with a balloon of CO followed by theaddition of DMF (5 mL), MeOH (3 mL), and triethylamine (780 μL, 5.62mmol). The reaction mixture was heated to 65° C. under atmosphericpressure of CO for 3 h. Upon completion, the reaction mixture was cooledto 0° C. and water (3 mL) was added. The resulting solid was collectedby filtration, washed with hexanes, and dried under vacuum before takingon directly to the next step without further purification. LCMScalculated for C12H₉BrN₃O₂ (M+H)⁺: m/z=306.0/308.0; found: 305.9/307.9.

Step 4. Methyl9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxylate

A vial containing methyl9-bromoimidazo[2,1-f][1,6]naphthyridine-3-carboxylate (150 mg, 0.490mmol),1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(164 mg, 0.588 mmol), potassium phosphate, tribasic (312 mg, 1.47 mmol),and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (36 mg,0.05 mmol) was evacuated and backfilled with nitrogen three times,followed by the addition of 1,4-dioxane (2 mL) and water (200 μL). Thevial was sealed and heated to 80° C. for 1 h. After cooling to roomtemperature, the mixture was diluted with CH₂Cl₂, filtered throughCelite and concentrated in vacuo. The obtained crude product was used inthe next step without further purification. LCMS calculated forC₂₀H₂₀N₅O₃ (M+H)⁺: m/z=378.2; found: 378.1.

Step 5.9-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide

To a vial containing methyl9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxylate(17 mg, 0.045 mmol) and LiOH (11 mg, 0.45 mmol) was added THF (250 μL)and water (750 μL). The reaction mixture was stirred at 60° C. for 1 hand, upon completion, excess water was added. The resulting precipitatewas subsequently filtered off. The pH of the filtrate was then adjustedto ˜5 with 1N HCl and the resulting precipitate was collected byfiltration and dried under vacuum. The crude solid was then dissolved inTHF (500 μL) followed by the addition of thionyl chloride (20 μL, 0.275mmol) and 1 drop of DMF. The resulting suspension was warmed to 45° C.for 2 h and, upon completion, the volatiles were removed in vacuo. Thecrude residue was dissolved in THF (500 μL) and an ammonium hydroxidesolution (50 μL, 1.3 mmol) was added. The reaction mixture was stirredat room temperature for 5 min at which point the solution was dilutedwith acetonitrile and aqueous TFA then purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.10% TFA, at flow rate of 60 mL/min) to provide the title compound as aTFA salt. LCMS calculated for C₁₉H₁₉N₆O₂ (M+H)⁺: m/z=363.2; found 363.1.¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (d, J=7.6 Hz, 1H), 9.32 (d, J=2.3 Hz,1H), 9.00 (d, J=2.3 Hz, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 8.26 (s, 1H),7.49 (d, J=7.7 Hz, 1H), 4.48 (tt, J=10.3, 4.7 Hz, 1H), 4.06-3.96 (m,2H), 3.52 (td, J=11.6, 2.7 Hz, 2H), 2.17-1.93 (m, 4H).

Example A: FGFR Enzymatic Assay

The inhibitor potency of the exemplified compounds was determined in anenzyme discontinuous assay that measures peptide phosphorylation usingFRET measurements to detect product formation. Inhibitors were seriallydiluted in DMSO and a volume of 0.2 μL was transferred to the wells of a384-well plate. A 5 μL/well volume of enzyme isoforms of FGFR (-1, -2,-3 wild-type and mutant isoforms, -4) including phosphorylated andun-phosphorylated proteins diluted in assay buffer (50 mM HEPES, 10 mMMgCl₂, 1 mM EGTA, 0.01% Tween-20, 5 mM DTT, pH 7.5) was added to theplate and pre-incubated with inhibitor for 5 to 15 minutes at ambienttemperature. Appropriate controls (enzyme blank and enzyme with noinhibitor) were included on the plate. The reaction was initiated by theaddition of a 5 μL/well volume containing both biotinylatedEQEDEPEGDYFEWLE peptide substrate (SEQ ID NO: 1) and ATP in assaybuffer. The 10 μL/well reaction concentration of the peptide substratewas 500 nM whereas the ATP concentration was maintained near or belowthe ATP Km. The ATP Km values were pre-determined in a separate seriesof experiments. The reaction plate was incubated at 25° C. for 1 hr andthe reactions were ended with the addition of 5 μL/well of quenchsolution (50 mM Tris, 150 mM NaCl, 0.5 mg/mL BSA, pH 7.8; 45 mM EDTA,600 nM staurosporin, with Perkin Elmer Lance Reagents at 3.75 nMEu-antibody PY20 and 180 nM APC-Streptavidin). The plate was allowed toequilibrate for ˜10 minutes at ambient temperature before scanning on aPheraStar plate reader (BMG Labtech) instrument.

Either GraphPad prism or XLfit was used to analyze the data. The IC₅₀values were derived by fitting the data to a four parameter logisticequation producing a sigmoidal dose-response curve with a variable Hillcoefficient. Prism equation: Y=Bottom+(Top−Bottom)/(1+10{circumflex over( )}((Log IC₅₀−X)*Hill slope)); XLfit equation:Y=(A+((B−A)/(1+((X/C){circumflex over ( )}D)))) where X is the logarithmof inhibitor concentration and Y is the response. Compounds having anIC₅₀ of 1 μM or less are considered active.

Table 1 provides IC₅₀ data for compounds of the disclosure assayed inthe FGFR Enzymatic Assay after dilution in assay buffer, added to theplate and pre-incubated for 4 hours. The symbol: “+” indicates an IC₅₀less than 0.1 nM; “++” indicates an IC₅₀ greater than or equal to 0.1 nMbut less than 1.0 nM; “+++” indicates an IC₅₀ greater than or equal to1.0 nM but less than 10 nM; and “++++” indicates an IC₅₀ greater than orequal to 10 nM but less than 50 nM.

The data in Table 1 was measured in wild-type un-phosphorylated FGFR3protein.

TABLE 1 FGFR3 IC₅₀ Example No. (nM) 1 + 2 + 3 ++ 4 + 5 + 6 + 7 ++ 8 +9 + 10 + 11 + 12 ++ 13 ++ 14 + 15 + 16 + 17 + 18 + 19 + 20 ++ 21 + 22 +23 + 24 ++ 25 ++ 26 + 27 + 28 + 29 + 30 + 31 + 32 + 33 + 34 + 35 + 36 +37 + 38 +++ 39 ++ 40 +++ 41 ++ 42 +++ 43 ++ 44 + 45 ++ 46 ++ 47 + 48 +49 + 50 ++ 51 ++ 52 ++ 53 + 54 ++ 55 ++++ 56 +++ 57 ++++ 58 ++++

Example B: Luminescent Viability Assay

RT112 cells (cell lines and genetic profiles further detailed in Table3) are purchased from ATCC (Manassas, Va.) and maintained in RPMI, 10%FBS (Gibco/Life Technologies). To measure the effect of test compoundson the viability of cells, the cells are plated with RPMI 10% FBS (5×103cells/well/in 50 □L) into black 96-well Greiner polystyrene in thepresence or absence of 50 ul of a concentration range of test compounds.After 3 days, 100 ul of CellTiter-Glo Reagent (Promega) is added.Luminescence is read with a TopCount (PerkinElmer). IC₅₀ determinationis performed by fitting the curve of percent inhibition versus the logof the inhibitor concentration using the GraphPad Prism 5.0 software.

TABLE 3 Cell line Histology FGFR2/3 alteration RT-112/84 BladderFGFR3-TACC3 RT112 Bladder FGFR3-TACC3 RT-112 V555M* Bladder FGFR3-TACC3V555M UM-UC-14 Bladder FGFR3 S249C RT-4 Bladder FGFR3-TACC3 SW-780Bladder FGFR3-BAIAP2L1 KMS-11 Multiple IgH-FGFR3 Myeloma translocation +FGFR3 Y373C OPM-2 Multiple IgH-FGFR3 Myeloma translocation + FGFR3 K650EKATO-III Stomach FGFR2 amplification SNU-16 Stomach FGFR2 amplificationAN3CA Endometrial FGFR2 N310R/N549K Ba/F3-FGFR2-BICC1 EngineeredFGFR2-BICC1** system Ba/F3-TEL-FGFR3 Engineered TEL-FGFR3 systemBa/F3-TEL-FGFR3 V555M Engineered TEL-FGFR3 V555M system Ba/F3-TEL-FGFR3V555L Engineered TEL-FGFR3 V555L system *RT112 V555M: V555M mutation wasengineered using CRISPR-mediated genome editing. **FGFR2-BICC1 fusionrepresents the most prevalent FGFR2 alteration in cholangiocarcinoma

Example C: pFGFR2 and pFGFR1,3 Functional Cell HTRF Assay

To measure phosphorylated Fibroblast Growth Factor Receptor 2 (FGFR2),KATOIII cells (Human Gastric Carcinoma) are purchased from ATCC andmaintained in Iscove's with 20% FBS (Gibco/Life Technologies). For thepFGFR2 assay, KiATOIII cells are plated overnight in 500 FBS andIscove's medium at 5×10⁴ cells/well into Corning 96-well flat-bottomtissue culture treated plates. The next morning, 50 μl of fresh mediawith 0.5% FBS is incubated in the presence or absence of a concentrationrange of test compounds also at 50 ul, for 1 hour at 37° C., 5% C02.Cell are washed with PBS, lysed with Cell Signaling Lysis Buffer withstandard Protease inhibitors for 45 min at room temperature. 4 μl totalof Cis Bio Anti Phospho-YAP d2 and Cis Bio Anti Phospho-YAP Cryptatetogether are added to the lysate and mixed well (following directions ofthe kit). 16 μl is then transferred to 384 well Greiner white plates andstored at 4° C. overnight in the dark. Plates are read on the Pherastarplate reader at 665 nm and 620 nm wavelengths. IC₅₀ determination isperformed by fitting the curve of inhibitor percent inhibition versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

To measure phosphorylated Fibroblast Growth Factor Receptor 3 (FGFR3),in house stable cell lines BAF3-TEL-FGFR1 or BAF3-TEL-FGFR3 aremaintained in RPMI with 10% FBS and 1 ug/ml puromycin (Gibco/LifeTechnologies). For the assay, 12 nl of BAF3-TEL-FGFR1 or BAF3-TEL-FGFR3cells in serum free and puromycin free RPMI media at 1×10⁶ cell/ml areadded to 384 Greiner white plate already containing 20 nl dots ofcompounds at a concentration range. The plates are gently shaken (100rpm) for 2 minutes at room temperature to mix well and incubate for 2hours in a single layer at 37° C., 5% CO2. 4 μl/well of 1/25 dilution oflysis buffer #3 (Cis Bio) is added with standard Protease inhibitors andshaken at 200 rpm at room temperature for 20 minutes. 4 μl total of theCis Bio Tb-pFGFR Ab (10 ng) and d2-FGFR3 (1 ng) together are added tothe lysate and mixed well. The plates are sealed and incubated at roomtemperature overnight in the dark. The plates are read on the Pherastarplate reader at 665 nm and 620 nm wavelengths. IC₅₀ determination isperformed by fitting the curve of inhibitor percent inhibition versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

Example D: pFGFR3 Functional Whole Blood HTRF Assay

To measure phosphorylated Fibroblast Growth Factor Receptor 3 (FGFR3) ina whole blood assay, in house stable cell lines BAF3-TEL-FGFR3 aremaintained in RPMI with 10% FBS and 1 μg/ml puromycin (Gibco/LifeTechnologies). For the assay, 100 ul BAF3-TEL-FGFR3 cells in 10% FBS andpuromycin free RPMI media at 5×10⁴ cell/well are added to fibronectincoated 96 well tissue culture plate (5 ug/ml) overnight at 37° C., 5%CO2. The next day, serum is separated from the top of the blood by a lowspeed spin, 1200, RPM, and heat inactivated by incubating at 56° C. for15 minutes. 30 μl of the cooled serum is added to a 96 well plate predotted with 70 nM dots of compounds at a concentration range. Cellplates are washed gently with media, all the blood/compound mixture isadded to the plates, and the plates are incubated for 2 hours at 37° C.,5% CO2. Blood from the plate is gently washed twice by adding media tothe side of the wells and then dumping media from the plate, andallowing the plate to briefly sit on a paper towel to drain. 70 μl/wellof 1× of lysis buffer #1 (Cis Bio) are added with standard Proteaseinhibitors, and are shaken at 400 rpm at room temperature for 30minutes. Following lysis, the plate is spun down for 5 minutes and 16 uLof lysate is transferred into a 384-well small volume plate. 4 μl totalof the Cis Bio Tb-pFGFR Ab (10 ng) and d2-FGFR3 (1 ng) together areadded to the lysate and mixed well. The plates are sealed and incubatedat room temperature overnight in the dark. Plates are read on thePherastar plate reader at 665 nm and 620 nm wavelengths. IC₅₀determination is performed by fitting the curve of inhibitor percentinhibition versus the log of the inhibitor concentration using theGraphPad Prism 5.0 software.

Example E: KATOIII Whole Blood pFGFR2α ELISA Assay

To measure tyrosine-phosphorylated Fibroblast Growth Factor Receptor 2alpha (FGFR2α) in KATO III spiked whole blood assay, KATO III cells arepurchased from ATCC and maintained in Iscove's medium with 20% FBS(Gibco/Life Technologies). To measure the inhibition of FGFR2a activityof test compounds, the cells are resuspended with Iscove's, 0.2% FBS at5×10⁶ cells/ml. 50 μL of the cells are then spiked into a 96-deep well 2ml polypropylene assay block (Costar,) in the presence or absence of aconcentration range of test compounds and 300 ul human heparinized wholeblood (Biological Specialty Corp, Colmar Pa.). After 4 hours incubationin 37° C., the red cells are lysed using Qiagen EL buffer and the celllysates are resuspended in lysis buffer (Cell Signaling) containingstandard protease inhibitor cocktail (Calbiochem/EMD,) and PMSF (Sigma)for 30 minutes ice. The lysates are transferred to a standard V bottompropylene tissue culture plate and frozen overnight at −80° C. Samplesare tested an in an R & D Systems DuoSet IC Human Phospho-FGF R2a ELISAand the plate is measured using a SpectraMax M5 microplate set to 450 nmwith a wavelength correction of 540. IC₅₀ determination is performed byfitting the curve of inhibitor percent inhibition versus the log of theinhibitor concentration using the GraphPad Prism 5.0 software.

Example F: Inhibition of FGFR Pathway

The cellular potency of compounds is determined by measuringphosphorylation of FGFR or FGFR downstream effectors Fibroblast growthfactor receptor substrate 2 (FRS2) and extracellular-signal-regulatedkinase (ERK) in cell lines with FGFR2/3 alterations.

To measure phosphorylated Fibroblast growth factor receptor, Fibroblastgrowth factor receptor substrate 2 (FRS2) andextracellular-signal-regulated kinase (ERK) cells (details regarding thecell lines and types of data produced are further detailed in Table 4)are seeded in 6 well plates overnight in 10% FBS and RPMI medium at5-7.5×10⁵ cells/well into Corning 6-well tissue culture treated plates.The next morning, 2 ml of fresh media with 10% FBS is incubated in thepresence or absence of a concentration range of test compounds for 4hours at 37° C., 5% CO2. Cells are washed with PBS and lysed with CellSignaling Lysis Buffer with standard Protease inhibitors. 20-40 μg oftotal protein lysates are applied to western blot analysis usingantibodies: phosphor-FRS2 Tyr436 (AF5126) from R&D Systems (Minneapolis,Minn.)), phosphor-FGFR-Tyr653/654 (#2476S), phospho-ERK1/2-Thr202/Tyr204(#9101L) and total-ERK1/2 (#9102L) from Cell Signaling Technologies(Danvers, Mass.)).

TABLE 4 FGFR2/3 Cell line Histology alteration Readout RT-112/84 BladderFGFR3-TACC3 pFRS2, pERK RT112 V555M Bladder FGFR3-TACC3 pFRS2, pERKV555M UM-UC-14 Bladder FGFR3 S249C pFRS2, pERK KMS-11 Multiple IgH-FGFR3pFRS2, pERK Myeloma translocation + FGFR3 Y373C KATO-III Stomach FGFR2pFGFR, pERK amplification SNU-16 Stomach FGFR2 pFGFR, pERK amplification

Example G: Activity on In Vivo Tumor Models Harboring FGFR2/3 Alteration

In vivo activity of compounds is determined by measuring tumor growthwhen treated with various doses of compounds in FGFR2/3 altered models.

RT112/84 tumor cells (85061106, ECACC, UK) are maintained as recommendedby the source (tumor models are further detailed in Table 5). On Day 0of the experiments, 2.0×10⁶ RT112/84 cells are inoculated with a 1:1 PBSto Matrigel (354263, Corning) subcutaneously into the right hind flankof female NSG mice (Jackson). Treatment with compounds at 0 (Vehicle),100 mg/kg, 30 mg/kg or 10 mg/kg PO QD is initiated on Day 7 after tumorinoculation, when tumors averaged approximately 200 mm³, and iscontinued until the end of study. Mice are monitored for tumor growthand overt tolerability over the course of the experiment. Tumor volumeis calculated using the formula (L×W²)/2, where L and W refer to thelength and width dimensions, respectively. Tumor growth inhibition (TGI)is calculated using the formula (1−(V_(T)/V_(C)))*100 where V_(T) is thetumor volume of the treatment group on the last day of treatment, andV_(C) is the tumor volume of the control group on the last day oftreatment. One-way ANOVA is used to determine statistical differencesbetween treatment groups at the end of the study.

TABLE 5 Tumor model Histology FGFR2/3 alteration RT-112/84 BladderFGFR3-TACC3 RT112 V555M Bladder FGFR3-TACC3 V555M UM-UC-14 Bladder FGFR3S249C KMS-11 Multiple Myeloma IgH-FGFR3 translocation + FGFR3 Y373CKATO-III Stomach FGFR2 amplification SNU-16 Stomach FGFR2 amplificationBa/F3-TEL- Engineered system TEL-FGFR3 V555M FGFR3 V555M

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹⁰; R² isselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(b2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(b2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NOW)R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2) S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²⁰; R³ isselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NOR^(a3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R³⁰; R⁴ isselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NOR^(a4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁴⁰; R⁵ isselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NOR^(a5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁵⁰; Z is N orCR⁶; R⁶ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6), C(═NR^(e6))R^(b6),C(═NOR^(a6))R^(b6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁶⁰; each R¹⁰ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a10), SR^(a10),C(O)R^(b10), C(O)NR^(c10)R^(d10), C(O)OR^(a10), OC(O)R^(b10),OC(O)NR^(c10)R^(d10), NR^(c10)R^(d10), NR^(c10)C(O)R^(b10),NR^(c10)C(O)OR^(a10), NR^(c10)C(O)NR^(c10)R^(d10), C(═NR^(e10))R^(b10),C(═NOR^(a10))R^(b10), C(═NR^(e10))NR^(c10)R^(d10),NR^(c10)C(═NR^(e10))NR^(c10)R^(d10), NR^(c10)S(O)R^(b10),NR^(c10)S(O)₂R^(b10), NR^(c10)S(O)₂NR^(c10)R^(d10), S(O)R^(b10),S(O)NR^(c10)R^(d10), S(O)₂R^(b10), and S(O)₂NR^(c10)R^(d10); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; each R¹¹ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a11), SR^(a11), C(O)R^(b11),C(O)NR^(c11)R^(d11), C(O)OR^(a11), NR^(c11)R^(d11), NR^(c11)C(O)R^(b11),NR^(c11)C(O)OR^(a11), NR^(c11)C(O)NR^(c11)R^(d11), NR^(c11)S(O)R^(b11),NR^(c11)S(O)₂R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11), S(O)R^(b11),S(O)NR^(c11)R^(d11), S(O)₂R^(b11), and S(O)₂NR^(c11)R^(d11); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²; each R¹² is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,halo, D, CN, OR^(a12), SR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12),C(O)OR^(a12), NR^(c12)R^(d12), NR^(c12)C(O)R^(b12),NR^(c12)C(O)OR^(a12), NR^(c12)C(O)NR^(c12)R^(d12), NR^(c12)S(O)R^(b12),NR^(c12)S(O)₂R¹², NR^(c12)S(O)₂NR^(c12)R^(d12), S(O)R^(b12),S(O)NR^(c12)R^(d12), S(O)₂R¹², and S(O)₂NR^(c12)R^(d12); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R²⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a20), SR^(a20), C(O)R^(b20), C(O)NR^(c20)R^(d20),C(O)OR^(b20), OC(O)R^(b20), OC(O)NR^(c20)R^(d20), NR^(c20)R^(d20),NR^(c20)C(O)R^(b20), NR^(c20)C(O)OR^(a20), NR^(c20)C(O)NR^(c20)R^(d20),C(═NR^(e20))R^(b20), C(═NOR^(a20))R^(b20), C(═NR^(e20))NR^(c20)R^(d20),NR^(c20)C(═NR^(e20))NR^(c20)R^(d20), NR^(c20)S(O)R^(b20),NR^(c20)S(O)₂R^(b20), NR^(c20)S(O)₂NR^(c20)R^(d20), S(O)R^(b20),S(O)NR^(c20)R^(d20), S(O)₂R^(b20), and S(O)₂NR^(c20)R^(d20); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹; each R²¹ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR²¹, SR^(a21), C(O)R^(b21),C(O)NR^(c21)R^(d21), C(O)OR^(a21), NR^(c21)R^(d21), NR^(c21)C(O)R^(b21),NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21), NR^(c21)S(O)R^(b21),NR^(c21)S(O)₂R^(b21), NR^(c21)S(O)₂NR^(c21)R^(d21), S(O)R^(b21),S(O)NR^(c21)R^(d21), S(O)₂R^(b21), and S(O)₂NR^(c21)R^(d21); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²; each R²² is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,CN, OR^(a22), SR^(a22), C(O)R^(b22), C(O)NR^(c22)R^(d22), C(O)OR^(a22),NR^(c22)R^(d22), NR^(c22)C(O)R^(b22), NR^(c22)C(O)OR^(a22),NR^(c22)C(O)NR^(c22)R^(d22), NR^(c22)S(O)R^(b22), NR^(c22)S(O)₂R^(b22),NR^(c22)S(O)₂NR^(c22)R^(d22), S(O)R^(b22), S(O)NR^(c22)R^(d22),S(O)₂R^(b22), and S(O)₂NR^(c22)R^(d22); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryland 4-7 membered heterocycloalkyl, are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R^(g); each R³⁰is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a30), SR^(a30),C(O)R^(b30), C(O)NR^(c30)R^(d30), C(O)OR^(a30), OC(O)R^(b30),OC(O)NR^(c30)R^(d30), NR^(c30)R^(d30), NR^(c30)C(O)R^(b30),NR^(c30)C(O)OR^(a30), NR^(c30)C(O)NR^(c30)R^(d30), C(═NR^(e30))R^(b30),C(═NOR^(a30))R^(b30), C(═NR^(e30))NR^(c30)R^(d30),NR^(c30)C(═NR^(e30))NR^(c30)R^(d30), NR^(c30)S(O)R^(b30),NR^(c30)S(O)₂R^(b30), NR^(c30)S(O)₂NR^(c30)R^(d30), S(O)R^(b30),S(O)NR^(c30)R^(d30), S(O)₂R^(b30), and S(O)₂NR^(c30)R^(d30); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³¹; each R³¹ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a31), SR^(a31), C(O)R^(b31),C(O)NR^(c31)R^(d31), C(O)OR^(a31), NR^(c31)R^(d31), NR^(c31)C(O)R^(b31),NR^(c31)C(O)OR^(a31), NR^(c31)C(O)NR^(c31)R^(d31), NR^(c31)S(O)R^(b31),NR^(c31)S(O)₂R^(b31), NR^(c31)S(O)₂NR^(c31)R^(d31), S(O)R^(b31),S(O)NR^(c31)R^(d31), S(O)₂R^(b31), and S(O)₂NR^(c31)R^(d31); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³²; each R³² is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,halo, D, CN, OR^(a32), SR^(a32), C(O)R^(b32), C(O)NR^(c32)R^(d32),C(O)OR^(a32), NR^(c32)R^(d32), NR^(c32)C(O)R^(b32),NR^(c32)C(O)OR^(a32), NR^(c32)C(O)NR^(c32)R^(d32), NR^(c32)S(O)R^(b32),NR³²S(O)₂R^(b32), NR^(c32)S(O)₂NR^(c32)R^(d32), S(O)R^(b32),S(O)NR^(c32)R^(d32), S(O)₂R^(b32), and S(O)₂NR^(c32)R^(d32); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R⁴⁰ is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a40), SR^(a40),C(O)R^(b40), C(O)NR^(c40)R^(d40), C(O)OR^(a40), OC(O)R^(b40),OC(O)NR^(c40)R^(d40), NR^(c40)R^(d40), NR^(c40)C(O)R^(b40),NR^(c40)C(O)OR^(a40), NR^(c40)C(O)NR^(c40)R^(d40), C(═NR^(e40))R^(b40),C(═NOR^(a40))R^(b40), C(═NR^(e40))NR^(c40)R^(d40),NR^(c40)C(═NR^(e40))NR^(c40)R^(d40), NR^(c40)S(O)R^(b40),NR^(c40)S(O)₂R^(b40), NR^(c40)S(O)₂NR^(c40)R^(d40), S(O)R^(b40),S(O)NR^(c40)R^(d40), S(O)₂R^(b40), and S(O)₂NR^(c40)R^(d40); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴¹; each R⁴¹ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a41), SR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), C(O)OR^(a41), NR^(c41)R^(d41), NR^(c41)C(O)R^(b41),NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41), NR^(c41)S(O)R^(b41),NR^(c41)S(O)₂R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)R^(b41),S(O)NR^(c41)R^(d41), S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴²; each R⁴² is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,halo, D, CN, OR^(a42), SR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42),C(O)OR^(a42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42),NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42), NR^(c42)S(O)R^(b42),NR^(c42)S(O)₂R^(b42), NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)R^(b42),S(O)NR^(c42)R^(d42), S(O)₂R^(b42), and S(O)₂NR^(c42)R^(d42); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R⁵⁰ is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a50), SR^(a50),C(O)R^(b50), C(O)NR^(c50)R^(d50), C(O)OR^(a50), OC(O)R^(b50),OC(O)NR^(c50)R^(d50), NR^(c50)R^(d50), NR^(c50)C(O)R^(b50),NR^(c50)C(O)OR^(a50), NR^(c50)C(O)NR^(c50)R^(d50), C(═NR^(e50))R^(b50),C(═NOR^(a50))R^(b50), C(═NR^(e50))NR^(c50)R^(d50),NR^(c50)C(═NR^(e50))NR^(c50)R^(d50), NR^(c50)S(O)R^(b50),NR^(c50)S(O)₂R^(b50), NR^(c50)S(O)₂NR^(c50)R^(d50), S(O)R^(b50),S(O)NR^(c50)R^(d50), S(O)₂R^(b50), and S(O)₂NR^(c50)R^(d50); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁵¹; each R⁵¹ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a51), SR^(a51), C(O)R^(b51),C(O)NR^(c51)R^(d51), C(O)OR^(a51), NR^(c51)R^(d51), NR^(c51)C(O)R^(b51),NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51), NR^(c51)S(O)R^(b51),NR^(c51)S(O)₂R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)R^(b51),S(O)NR^(c51)R^(d51), S(O)₂R^(b51), and S(O)₂NR^(c51)R^(d51); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁵²; each R⁵² is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,halo, D, CN, OR^(a52), SR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)OR^(a52)NR^(c52)R^(d52), NR^(c52)C(O)R^(b52), NR^(c52)C(O)OR^(a52),NR^(c52)C(O)NR^(c52)R^(d52), NR^(c52)S(O)R^(b52), NR^(c52)S(O)₂R^(b52),NR^(c52)S(O)₂NR^(c52)R^(d52), S(O)R^(b52), S(O)NR^(c52)R^(d52),S(O)₂R^(b52), and S(O)₂NR^(c52)R^(d52); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R⁶⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a60), SR^(a60), C(O)R^(b60), C(O)NR^(c60)R^(d60),C(O)OR^(a60), OC(O)R^(a60), OC(O)NR^(c60)R^(d60), NR^(c60)R^(d60),NR^(c60)C(O)R^(b60), NR^(c60)C(O)OR^(a60), NR^(c60)C(O)NR^(c60)R^(d60),C(═NR^(e60))R^(b60), C(═NOR^(a60))R^(b60), C(═NR^(e60))NR^(c60)R^(d60),NR^(c60)C(═NR^(e60))NR^(c60)R^(d60), NR^(c60)S(O)R^(b60),NR^(c60)S(O)₂R^(b60), NR^(c60)S(O)₂NR^(c60)R^(d60), S(O)R^(b60),S(O)NR^(c60)R^(d60), S(O)₂R^(b60), and S(O)₂NR^(c60)R^(d60); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁶¹; each R⁶¹ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a61), SR^(a61), C(O)R^(b61),C(O)NR^(c61)R^(d61), C(O)OR^(a61), NR^(c61)R^(d61), NR^(c61)C(O)R^(b61),NR^(c61)C(O)OR^(a61), NR^(c61)C(O)NR^(c61)R^(d61), NR^(c61)S(O)R^(b61),NR^(c61)S(O)₂R^(b61), NR^(c61)S(O)₂NR^(c61)R^(d61), S(O)R^(b61),S(O)NR^(c61)R^(d61), S(O)₂R^(b61), and S(O)₂NR^(c61)R^(d61); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁶²; each R⁶² is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,halo, D, CN, OR^(a62), SR^(a62), C(O)R^(b62), C(O)NR^(c62)R^(d62),C(O)OR^(a62), NR^(c62)R^(d62), NR^(c62)C(O)R^(b62),NR^(c62)C(O)OR^(a62), NR^(c62)C(O)NR^(c62)R^(d62), NR^(c62)S(O)R^(b62),NR^(c62)S(O)₂R^(b62), NR^(c62)S(O)₂NR^(c62)R^(d62), S(O)R^(b62),S(O)NR^(c62)R^(d62), S(O)₂R^(b62), and S(O)₂NR^(c62)R^(d62); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(a1), R^(b1), R^(c1) andR^(d1) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰; or any R^(c1) and R^(d1) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹⁰; each R^(e1) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a2), R^(b2), R^(c2) and R^(d2) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R²⁰; or anyR^(c2) and R^(d2) attached to the same N atom, together with the N atomto which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²⁰; each R^(e2) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a3), R^(b3), R^(c3) and R^(d3) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R³⁰; or anyR^(c3) and R^(d3) attached to the same N atom, together with the N atomto which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R³⁰; each R^(e3) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a4), R^(b4), R^(c4) and R^(d4) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁴⁰; or anyR^(c4) and R^(d4) attached to the same N atom, together with the N atomto which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁴⁰; each R^(e4) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a5), R^(b5), R^(c5) and R^(d5) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁵⁰; or anyR^(c5) and R^(d5) attached to the same N atom, together with the N atomto which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵⁰; each R^(e5) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a6), R^(b6), R^(c6) and R^(d6) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁶⁰; or anyR^(c6) and R^(d6) attached to the same N atom, together with the N atomto which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁶⁰; each R^(e6) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a10), R^(b10), R^(c10) and R^(d10) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹¹; or anyR^(c10) and R^(d10) attached to the same N atom, together with the Natom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹; each R^(e10) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a11), R^(b11), R^(c11) and R^(d11) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²; or any R^(c11) andR^(d11) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R¹²; each R^(a12), R^(b12), R^(c12) and R^(d12) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(a20), R^(b20), R^(c20) andR^(d20) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹; or any R^(c20) and R^(d20) attached to the same Natom, together with the N atom to which they are attached, form a 4-,5-, 6- or 7-membered heterocycloalkyl group optionally substituted with1, 2, 3, or 4 substituents independently selected from R²¹; each R^(e20)is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a21), R^(b21), R^(c21) and R^(d21) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R²²; or any R^(c21) andR^(d21) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R²²; each R^(a22), R^(b22), R^(c22) and R^(d22) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(a30), R^(b30), R^(c30) andR^(d30) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³¹; or any R^(c30) and R^(d30) attached to the same Natom, together with the N atom to which they are attached, form a 4-,5-, 6- or 7-membered heterocycloalkyl group optionally substituted with1, 2, 3, or 4 substituents independently selected from R³¹; each R^(e30)is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a31), R^(b31), R^(c31) and R^(d31) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R³²; or any R^(c31) andR^(d31) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R³²; each R^(a32), R^(b32), R^(c32) and R^(d32) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(a40), R^(b40), R^(c40) andR^(d40) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁴¹; or any R^(c40) and R^(d40) attached to the same Natom, together with the N atom to which they are attached, form a 4-,5-, 6- or 7-membered heterocycloalkyl group optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁴¹; each R^(e40)is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a41), R^(b41), R^(c41) and R^(d41) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R⁴²; or any R^(c41) andR^(d41) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R⁴²; each R^(a42), R^(b42), R^(c42) and R^(d42) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(a50), R^(b50), R^(c50) andR^(d50) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁵¹; or any R^(c50) and R^(d50) attached to the same Natom, together with the N atom to which they are attached, form a 4-,5-, 6- or 7-membered heterocycloalkyl group optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁵¹; each R^(e50)is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a51), R^(b51), R^(c51) and R^(d51) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R⁵²; or any R^(c51) andR^(d51) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R⁵²; each R^(a52), R^(b52), R^(c52) and R^(d52) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(a60), R^(b60), R^(c60) andR^(d60) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁶¹; or any R^(c60) and R^(d60) attached to the same Natom, together with the N atom to which they are attached, form a 4-,5-, 6- or 7-membered heterocycloalkyl group optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁶¹; each R^(e60)is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a61), R^(b61), R^(c61) and R^(d61) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R⁶²; or any R^(c61) andR^(d61) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R⁶²; each R^(a62), R^(b62), R^(c62) and R^(d62) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); and each R^(g) is independentlyselected from D, OH, NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C3.6 cycloalkyl, C3.6 cycloalkyl-C₁₋₂ alkylene,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl,amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkylcarbonyloxy,aminocarbonyloxy, C₁₋₆ alkylaminocarbonyloxy, di(C₁₋₆alkyl)aminocarbonyloxy, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Z is CR⁶.
 3. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, D, CN, NO₂, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰.
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰.
 5. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selectedfrom C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6membered heteroaryl; wherein said C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹⁰.
 6. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R¹ is selected from pyrazol-4-yl, imidazol-4-yl,6-oxo-1,6-dihydropyridin-3-yl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, pyridin-3-yl, andpyrimidin-5-yl, each of which is optionally substituted with 1 or 2substituents independently selected from R¹⁰.
 7. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein, R¹ ispyrazolyl optionally substituted with 1 or 2 substituents independentlyselected from R¹⁰.
 8. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein, R¹ is phenyl optionally substitutedwith 1 or 2 substituents independently selected from R¹⁰.
 9. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from H, 1-(2-hydroxyethyl)-1H-pyrazol-4-yl,1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl,1-(1-amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl,4-(morpholine-4-carbonyl)phenyl, 1H-pyrazol-4-yl,1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl,1-(2-hydroxybutyl)-1H-pyrazol-4-yl,1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl,1-((5-cyanopyridin-3-yl)methyl)-1H-pyrazol-4-yl,1-((2-cyanopyridin-4-yl)methyl)-1H-pyrazol-4-yl,1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl,1-(1-(2-cyanopyridin-4-yl)ethyl)-1H-pyrazol-4-yl,4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl,4-(1,1-dioxidothiomorpholino)phenyl,1-(pyrimidin-2-ylmethyl)-1H-pyrazol-4-yl,1-((6-cyanopyridin-2-yl)methyl)-1H-pyrazol-4-yl,4-(4-acetylpiperazin-1-yl)phenyl,4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl,4-((4-acetylpiperazin-1-yl)methyl)phenyl,4-((4-(2-hydroxyacetyl)piperazin-1-yl)methyl)phenyl,4-(4-methylpiperazin-1-yl)phenyl,4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl,1-(cyanomethyl)-1H-pyrazol-4-yl,1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, 1-benzyl-1H-pyrazol-4-yl,1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl,1-(1-cyanoethyl)-1H-pyrazol-4-yl, 1-(2,2-difluoroethyl)-1H-pyrazol-4-yl,1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl,1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl,1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl, 1-cyclopropyl-1H-pyrazol-4-yl,1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl,1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl,1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl,9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl,1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl,6-oxo-1,6-dihydropyridin-3-yl, 5-isopropyl-1H-pyrazol-4-yl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,5-(2-hydroxypropan-2-yl)pyridin-3-yl, 2-(methylamino)pyrimidin-5-yl,1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl,1-(2-morpholinoethyl)-1H-pyrazol-4-yl,1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl,1-(3-hydroxypropyl)-1H-pyrazol-4-yl, 1-(2-cyanoethyl)-1H-pyrazol-4-yl,1-(2-Amino-2-oxoethyl)-1H-pyrazol-4-yl,6-(2-hydroxypropan-2-yl)pyridin-3-yl,6-(2,2,2-trifluoroethyl)pyridin-3-yl, 6-(methylcarbamoyl)pyridin-3-yl,4-hydroxycyclohex-1-en-1-yl, 5-hydroxypent-1-yn-1-yl, and2-hydroxypropan-2-yl.
 10. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R¹⁰ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, D, CN, NO₂, OR^(a10), C(O)R^(b10),C(O)NR^(c10)R^(d10), C(O)OR^(a10), OC(O)R^(b10), NR^(c10)R^(d10),NR^(c10)C(O)R^(b10), S(O)₂R^(b10), and S(O)₂NR^(c10)R^(d10); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹.
 11. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R¹⁰ isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, OR^(a10),C(O)NR^(c10)R^(d10), and NR^(c10)R^(d10); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹.
 12. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, OR^(a10), C(O)NR^(c10)R^(d10), NR^(c10)R^(d10),1,1-dioxidotetrahydro-2H-thiopyranyl, 1,1-dioxidothiomorpholino,piperazinyl, tetrahydro-2H-pyranyl, piperidinyl, cyclopropyl,tetrahydrofuran-3-yl, and cyclohexenyl, each of which is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹.
 13. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, OR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11),NR^(c11)R^(d11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11), andS(O)₂NR^(c11)R^(d11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹².
 14. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachR¹¹ is independently selected from C₁₋₆ alkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, CN, OR^(a11),C(O)R^(b11), C(O)NR^(c11)R^(d11), NR^(c11)R^(d11), and S(O)₂R^(b11);wherein said C₁₋₆ alkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹².
 15. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹²is independently selected from C₁₋₆ alkyl, halo, CN, OR^(a12), andC(O)R^(b12); wherein said C₁₋₆ alkyl is optionally substituted with 1 or2 substituents independently selected from R^(g).
 16. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R² isselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, D, CN, NO₂, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).
 17. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R² is H.18. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R³ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), S(O)₂R³, andS(O)₂NR^(c3)R^(d3).
 19. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R³ is H.
 20. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R⁴ is selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D,CN, NO₂, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4).
 21. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is H.22. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁵⁰.
 23. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁵ is selected from H, C₁₋₆ alkyl, and C₆₋₁₀ aryl; wherein saidC₁₋₆ alkyl and C₆₋₁₀ aryl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R⁵⁰.
 24. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ isselected from C₁₋₆ alkyl, and phenyl; wherein said C₁₋₆ alkyl and phenylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁵⁰.
 25. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁵ is phenyloptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁵⁰.
 26. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is H, methyl or 2,6-dichlorophenyl.27. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R⁵⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a50), C(O)R^(b50), C(O)NR^(c50)R^(d50),C(O)OR^(a50), NR^(c50)R^(d50), NR^(c50)C(O)R^(b50), S(O)₂R^(b50), andS(O)₂NR^(c50)R^(d50).
 28. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R⁵⁰ is independently selected fromhalo.
 29. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R⁵⁰ is Cl.
 30. The compound of claim 1, whereinthe compound has Formula II:

or a pharmaceutically acceptable salt thereof.
 31. The compound of claim1, wherein the compound has Formula IIIa or Formula IIIb:

or a pharmaceutically acceptable salt thereof.
 32. The compound of claim1, wherein the compound has Formula IVa or Formula IVb:

or a pharmaceutically acceptable salt thereof.
 33. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein: R¹ isselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, D, CN, NO₂, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰; R² is H; R³ is H; R is H; R⁵ is selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,halo, D, CN, NO₂, OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁵⁰; Z is CR⁶; R⁶ is H; each R¹⁰ is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, D, CN, NO₂, OR^(a10), C(O)R^(b10),C(O)NR^(c10)R^(d10), C(O)OR^(a10), OC(O)R^(b10), NR^(c10)R^(d10),NR^(c10)C(O)R^(b10), S(O)₂R^(b10), and S(O)₂NR^(c10)R^(d10); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; each R¹¹ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, D, CN, OR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11),C(O)OR^(a11), NR^(c11)R^(d11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11), andS(O)₂NR^(c11)R^(d11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹²; each R¹² isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, halo, D, CN, OR^(a12), C(O)R^(b12),C(O)NR^(c12)R^(d12), C(O)OR^(a12), NR^(c12)R^(d12), NR^(c12)C(O)R^(b12),S(O)NR^(c12)R^(d12), S(O)₂R^(b12), and S(O)₂NR^(c12)R^(d12); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R⁵⁰ is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, D, CN, NO₂, OR^(a50), C(O)R^(b50),C(O)NR^(c50)R^(d50), C(O)OR^(a50), OC(O)R^(b50), NR^(c50)R^(d50),NR^(c50)C(O)R^(b50), S(O)₂R^(b50), and S(O)₂NR^(c50)R^(d50); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁵¹; each R⁵¹ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, D, CN, OR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51),C(O)OR^(a51), NR^(c51)R^(d51), NR^(c51)C(O)R^(b51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁵²; each R⁵² isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, halo, D, CN, OR^(a52), C(O)R^(b52),C(O)NR^(c52)R^(d52), C(O)OR^(a52), NR^(c52)R^(d52), NR^(c52)C(O)R^(b52),S(O)₂R^(b52), and S(O)₂NR^(c52)R^(d52); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R^(a1), R^(b1), R^(c1) and R^(d1) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰; or any R^(c1) and R^(d1)attached to the same N atom, together with the N atom to which they areattached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰; each R^(a5), R^(b5), R^(c5) and R^(d5) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁵⁰; or anyR^(c5) and R^(d5) attached to the same N atom, together with the N atomto which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵⁰; each R^(a10), R^(b10),R^(c10) and R^(d10) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹; or any R^(c10) and R^(d10) attached to the same Natom, together with the N atom to which they are attached, form a 4-,5-, 6- or 7-membered heterocycloalkyl group optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹; eachR^(a11), R^(b11), R^(c11) and R^(d11) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²; or any R^(c11) and R^(d11) attached tothe same N atom, together with the N atom to which they are attached,form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2 or 3 substituents independently selected from R¹²;each R^(a12), R^(b12), R^(c12) and R^(d12) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R^(a50), R^(b50), R^(c50) and R^(d50) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁵¹; or anyR^(c50) and R^(d50) attached to the same N atom, together with the Natom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁵¹; each R^(a51), R^(b51),R^(c51) and R^(d51) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁵²; or any R^(c51) and R^(d51) attached to the same N atom, togetherwith the N atom to which they are attached, form a 4-, 5-, 6- or7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R⁵²; each R^(a52), R^(b52),R^(c52) and R^(d52) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); and each R^(g) isindependently selected from D, OH, CN, halo, C₁₋₆ alkyl, and C₁₋₆haloalkyl.
 34. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein: R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰; R² is H; R³ is H; R⁴ is H;R⁵ is selected from H, C₁₋₆ alkyl, and C₆₋₁₀ aryl; wherein said C₁₋₆alkyl and C₆₋₁₀ aryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁰; Z is CR⁶; R⁶ is H; each R¹⁰is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, OR^(a10),C(O)NR^(c10)R^(d10), and NR^(c10)R^(d10); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹; each R¹¹ is independently selected from C₁₋₆ alkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, CN, OR^(a11),C(O)R^(b11), C(O)NR^(c11)R^(d11), NR^(c11)R^(d11), and S(O)₂R^(b11);wherein said C₁₋₆ alkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²; each R¹² isindependently selected from C₁₋₆ alkyl, halo, CN, OR^(a12), andC(O)R^(b12); wherein said C₁₋₆ alkyl is optionally substituted with 1 or2 substituents independently selected from R^(g); each R⁵⁰ isindependently selected from halo; each R^(a10), R^(c10) and R^(d10) isindependently selected from H and C₁₋₆ alkyl; wherein said C16 alkyl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹; or any R^(c10) and R^(d10) attached to the same Natom, together with the N atom to which they are attached, form a 6- or7-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹; each R^(a11),R^(b11), R^(c11) and R^(d11) is independently selected from H and C₁₋₆alkyl; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²; each R^(a12) andR^(b12) is independently selected from H and C₁₋₆ alkyl; wherein saidC₁₋₆ alkyl is optionally substituted with R^(g); and R^(g) is OH. 35.The compound of claim 1, wherein the compound is selected from:2-(2,6-Dichlorophenyl)-9-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(1-(1-Amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(4-(morpholine-4-carbonyl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(1-(1-Cyanopropan-2-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(2-hydroxybutyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(1-((5-Cyanopyridin-3-yl)methyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(1-((2-Cyanopyridin-4-yl)methyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(1-(1-(2-Cyanopyridin-4-yl)ethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(4-(1,1-dioxidothiomorpholino)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(pyrimidin-2-ylmethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(1-((6-Cyanopyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(4-(4-Acetylpiperazin-1-yl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(4-((4-Acetylpiperazin-1-yl)methyl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(4-((4-(2-hydroxyacetyl)piperazin-1-yl)methyl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(4-(4-methylpiperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(4-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(1-(Cyanomethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(1-Benzyl-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(1-(1-Cyanoethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(1-(2-Cyanopropan-2-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(1-Cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-methyl-1H-imidazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(6-oxo-1,6-dihydropyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(5-isopropyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(2-(methylamino)pyrimidin-5-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(1-(2-Cyanoethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;9-(1-(2-Amino-2-oxoethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(6-(2,2,2-trifluoroethyl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(6-(methylcarbamoyl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(4-hydroxycyclohex-1-en-1-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(5-hydroxypent-1-yn-1-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)-9-(2-hydroxypropan-2-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-(2,6-Dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;2-Methyl-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide;and9-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide,or a pharmaceutically acceptable salt of any of the aforementioned. 36.A pharmaceutical composition comprising a compound of claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 37. A method of inhibiting an FGFR3enzyme comprising contacting said enzyme with a compound of claim 1 or apharmaceutically acceptable salt thereof.
 38. A method of treatingcancer in a patient comprising administering to said patient atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 39. A method of treatingcancer in a patient comprising administering to said patient atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof in combination with anothertherapy or therapeutic agent.
 40. The method of claim 38, wherein saidcancer is selected from adenocarcinoma, bladder cancer, breast cancer,cervical cancer, cholangiocarcinoma, colorectal cancer, endometrialcancer, esophageal cancer, gall bladder cancer, gastric cancer, glioma,head and neck cancer, hepatocellular cancer, kidney cancer, livercancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer,prostate cancer, rhabdomyosarcoma, skin cancer, thyroid cancer,leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cellleukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's ornon-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, hairy celllymphoma, and Burkett's lymphoma.
 41. The method of claim 38, whereinsaid cancer is selected from adenocarcinoma, bladder cancer, breastcancer, cervical cancer, cholangiocarcinoma, endometrial cancer, gastriccancer, glioma, head and neck cancer, lung cancer, ovarian cancer,leukemia, and multiple myeloma.
 42. A method for treating a skeletal orchondrocyte disorder in a patient comprising administering to saidpatient a therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 43. The method of claim 42,wherein said skeletal or chondrocyte disorder is selected fromachrondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia(TD), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome,Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, andcraniosynostosis syndrome.